combination therapy

2. Metabolic Syndrome &
HTN
Burden Free ….
Health Guarantee

3. Prof. Mahmoud Youssof
Professor of Cardiology,
Head of Cardiovascular Dep,
Mansoura University
You can contact me at:
myousif200@gmail.com

4. Definition
Constellation of metabolic abnormalities that confer
increased risk of cardiovascular disease(CVD) and
diabetes mellitus.

5. Alternative names
• Metabolic syndrome
• Syndrome X
• Insulin resistance syndrome
• Deadly quartet
• Reaven’s syndrome

6. International Diabetes Federation Definition:
Abdominal obesity plus two other components: elevated BP, low HDL, elevated TG, or
impaired fasting glucose

7. The major features of metabolic syndrome include
Central obesity
Hypertrilgyceridemia
Low high density lipoprotein (HDL)
Hyperglycemia
hypertension

8. EPIDEMIOLOGY
• Prevalence increases with age
• Greater industrialization and urbanization
• Increase in waist circumference is found predominantly in women.
• Fasting TG>150 mg/dl and hypertension more likely in men.

9. Risk factors
• Overweight/ obesity- central (key feature)
• Sedentary lifestyle
Predictor of CVd events and associted mortality
Associated with central obesity, TG’s, HDL, BP, glucose intolerance
• Aging- prevalence increases with age
• Diabetes mellitus- approx. 75% of T2DM or IGT have metabolic syndrome
• Coronary heart disease- 50% of CHD patients have metabolic syndrome
•
• About 1/3rd of MS patients have premature CAD
• Lipodystrophy- both genetic or acquired have severe insulin resistance

10. CLINICAL FEATURES
• Usually asymptomatic and a high index of suspicion is needed for
diagnosis
• Examination -
Increased waist circumference
Increased Blood Pressure
Lipoatrophy
Acanthosis nigricans/ skin tags
Should alert to search
for other abnormalities

11. Metabolic
Syndrome
Burden Free ….
Health
Guarantee
Hypertension Diabetes

12. Why to treat ?

14. Complications of Hypertension:
End-Organ Damage
Chobanian AV, et al. JAMA. 2003;289:2560-2572.
Peripheral
Vascular
Disease
Renal Failure,
Proteinuria
LVH, CHD, CHF
Hemorrhage,
Stroke
Retinopathy
Hypertension

15. BP Reductions as Little as 2 mm Hg
Reduce the Risk of CV Events by Up to 10%
• Meta-analysis of 61 prospective, observational studies
• 1 million adults
• 12.7 million person-years
Lewington S et al. Lancet 2002;360:1903-1913.
2 mm Hg decrease
in mean SBP
10% reduction in risk of
stroke mortality
7% reduction in risk of
ischemic heart disease
mortality

16. BP Differences of 10 mmHg Are Associated With Up to a 40% Effect on
CV Risk
• Meta-analysis of 61 prospective, observational studies
• 1 million adults
• 12.7 million person-years
Lewington S et al. Lancet. 2002;360:1903–1913.
10 mmHg decrease
in mean SBP
40% reduction in risk
of stroke mortality
30% reduction in
risk of IHD mortality

17. Cardiovascular Continuum starts by Hypertension and ends with
death !!
Circulation. 2006;114:2850-2870

18. Cardiometabolic
risks factors
MI
HF
PAD
Stroke
Cardiovascular
Disease/Event
Disease progression
Renal Failure
AFib
Adapted from Volpe M, J Am Soc Nephrol. 2006;17:S36-S43; Adapted from Unger T, Am J Cardiol. 2002;89:3A-9A ; Adapted from Dzau V
and Braunwald E. Am Heart J. 1991;121:1244-1263.0
MAU: Microalbuminuria
CRP: C-Reactive Protein
GFR: Glomerular Filtration Rate
LVH: Left Ventricular Hypertrophy
LAD: Left Atrium Dilatation
MI: Myocardial Infarction
AFib: Atrial Fibrillation
HF: Heart
PAD: Peripheral Arterial Disease
Cardiac / vascular
Remodeling
Endothelial
Dysfunction
Fibrosis
Hypertension
Obesity
Dyslipidemia
Impaired glucose
tolerance
Cardio-Vascular Continuum
Early intervention
may reverse
disease progression
Markers of disease progression
LVH, MAU & CRP
DEATH
Early intervention & monitoring of disease progression markers may reverse
disease progression

19. 19
Effect of blood pressure control in type 2
diabetes (UKPDS)
Adapted from UKPDS Group. BMJ 1998;317:703–13
Progression
of
retinopathy
–60
–50
–40
–30
–20
0
Diabetes-
related
endpoints
Heart
failure
Microvascular
complications
Diabetes-
related
death Stroke
–10
–32%
p=0.0046 p=0.019 p=0.013 p=0.0092 p=0.0043 p=0.0038
–24%
–37%
–56%
–44%
–34%
Reduction
of
risk
resulting
from
tight
control
of
blood
pressure
(%)
Lowering of blood pressure by 10/5 mmHg systolic/diastolic

20. Blood pressure (ADA 2019)
• BP should be measured at every routine clinical visit.
• Patients found to have elevated BP (≥140/90) should
have BP confirmed using multiple readings, including
measurements on a separate day, to diagnose
hypertension.
• Most patients with DM & hypertension should be
treated to a SBP goal of <140 mmHg & a DBP goal of
<90 mmHg.
Diabetes Care Volume 42, Supplement 1, January 2019

22. ESC 2018/ New Hypertension Guidelines
What is new and what has changed in the 2018 ESC/ESH Arterial Hypertension Guidelines?

24. Angiotensinogen
Angiotensin I
Angiotensin II
Angiotensin III
Renin
ACE
Aminopeptidase
Non-ACE
(eg. Chymase
in heart)
Angiotensin 1-7
Releases ADH; ↑ PG;
Natriuretic; ↓ RVR;
↓ BP (brain stem inj.)
? Role in effects of ACEI
1 2 3 7 8 9 10
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2 3 7 8 9 10
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2 3 7 8
NH2-Arg-Val…Pro-Phe-COOH
2 3 7 8
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
+
1. ↓ Renal Perfusion
Pressure
2. ↓ Na at Macula
Densa cells
3. ↑ Sympathetic
nerve activity (ß-1)
±PG
The Renin-Angiotensin System

25. ANGIOTENSIN SYSTEM
Angiotensinogen
renin
Ang I
Ang II
Potentiation of
sympathetic activity
ACE
Kyninase
(enzyme)
BRADYKININ SYSTEM
kallikrein
kininogen
Bradykinin
Endothelium
Prostaglandin
NO
 platelet
aggregation
 SMC
mitogenesis
Vasodilation
Inactive
peptide
+
FGF
PDGF
+
+
 aldosterone release
Angiotensin / Bradykinin Systems

26. Angiotensin II
Vasoconstriction
Aldosterone
Secretion
Direct Renal
Sodium Retention
↑ Thirst
ADH Release
↑ Cardiac
Contractility
Sympathetic
Facilitation:
Central
Nerve terminal
(ganglionic ?)
Cardiac & Vascular
Hypertrophy
All known physiologic effects are mediated
by the angiotensin II type 1 receptor
ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE

27. Vasoconstriction
Inflammation
Remodelling
Thrombosis
Stimulates AT1 receptor
Releases endothelin and norepinephrine
Reduces nitric oxide bioactivity and produces peroxynitrite
Activates NADH/NADPH oxidase and produces superoxide anion
Induces expression of MCP-1, VCAM, TNF-α, IL-6
Activates monocytes/macrophages
Stimulates smooth muscle migration, hypertrophy and replication
Induces PDGF, bFGF, IGF-1, TGF-β expression
Stimulates matrix glycoprotein and metalloproteinase production
Stimulates PAI-1 synthesis and alters tPA/PAI-1 ratio
Activates platelets with increased aggregation and adhesion
Dzau VJ. Hypertension 2001;37:1047–52
NADH = nicotinamide adenine dinucleotide; NADPH = nicotinamide adenine dinucleotide phosphate-oxidase; MCP-1 =
monocyte chemoattractant protein-1;
VCAM = vascular cell adhesion molecule; TNF-α = tumour necrosis factor-α ;
IL-6 = interleukin-6; PDGF = platelet-derived growth factor; bFGF = basic fibroblast growth factor; IGF-1 = insulin-like
growth factor; TGF-β = transforming growth factor-β;
tPA = tissue-type plasminogen activator;
PAI-1 = plasminogen activator inhibitor type 1

29. McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.
Angiotensinogen
Angiotensin I
Angiotensin II
Renin
ACE
Aldosterone
(Adrenal/CV tissues)
Stroke HF
Kidney
failure
BP
VSMC
Fat cells
Reduced
baroreceptor
sensitivity

30. Atheroma formation and progression:
a struggle between death and regeneration
•Endothelial cells undergo suicide (apoptosis) and regenerate
•When a mismatch occurs, the endothelium loses its
continuity
Atherosclerosis ACS

31. Normal rate
of apoptosis: 3%
Maintenance of
endothelial layer
Excess rate of apoptosis
Onset of atherosclerotic
Protection against
atherosclerosis
Endothelial apoptosis and atherosclerosis
Plaque erosion and rupture
Endothelium continuity

32.  90% of ACE is a tissue enzyme present in the heart and vessel
( endothelium and smooth muscle )
 CAD up-regulates tissue ACE and alters the balance between:
Angiotensin II
Bradykinin
which, in turn, impairs endothelial function
ACE activity and endothelial function

33. WHY ?
• bradykinine (anti-apoptoic)
• angiotensin (pro-apoptoic)
• apoptoic inducer: TNF-
(ANTI)bradykinie angiotensin (PRO)

34. ACEIs
Vs. ARBs

35. Angiotensin II Antagonists
Advantages over ACE Inhibitors
 AT-1 receptors are blocked in all tissue (heart, vascular
endothelium, kidney and the brain) regardless of the alternative pathways of the
formation of Angiotensin II.
e.g. Chymase enzymes in the heart.
No dose adjustment is required in renal impaired patients
 No bradykinin accumulation, but normal bradykinin release is
present.
 No Cough
 Complete blockade of the pathological effects of Angiotensin II
through AT-1 receptor blockade.

36. Angiotensin II Antagonists
Advantages over ACE Inhibitors
Angiotensin II remaining in the tissues - in relative excess - fit in the
AT-2 receptors inducing beneficial effects
Vasodilatation
platelet aggregation;
proliferation of vascular SMC.
 Angiotensin II is converted to Angiotensin (1-7) which
stimulates “Nitric O” production directly irrespective of
bradykinin.
 “Nitric O” leads to a series of beneficial effects:
Vasodilatation
platelet aggregation
Anti - proliferate effect

37.  Specific selective blockade AT1-receptor
 Blocks also non-ACE produced A II
 Stimulation of the AT2-receptor
 No systemic increase Bradykinin
 Fewer side-effects with good safety profile
ARBs
Does It Affect Protection

38.  Cardiovascular Protection
 Decrease A F recurrence
 M0re LVH regression
 Renal Protection
 Cerebral Protection
 Reduction in Insulin Resistance-decrease incidence of
diabetes
E. Schmieder, AJH 2005; 18:720–730
Law et al.BMJ 2009;338;b 1665

41. Which
ARB?

42. Selectivity on AT1 Receptor With Different ARBs
Valsartan Candesartan Losartan
Irbesartan Telmisartan
10000
20000
30000 30,000
1000
8500
10,000 3,000
Valsartan is 3 times more selective for AT1 receptors than other ARB agents
Siragy H. Am J Cardiol. 1999;84:3S-8S.
Not all ARBs are the same
The more selectivity,
The more blockage of AT1receptors,
The more AngII will act on beneficial AT II

43. 21
1. VALUE
2. VALIANT
3. NAVIGATOR
4. Val-HeFT
5. JIKEI HEART
6. KYOTO HEART*
7. VART*
8. VALISH*
27. IDNT
28. ACTIVE-I*
29. NID-2
30. SUPPORT*
31. COLM*
32. OSCAR*
33. ORIENT*
34. MOSES
1. Julius et al. 2004; 2. Pfeffer et al. 2003; 3. Califf et al 2008; 4. Cohn et al. 2001; 5. Mochizuki et al. 2007;
6. http://clinicaltrials.gov (NCT00149227); 7. Nakayama et al. 2008; 8. NCT00151229; 9. ONTARGET Investigators 2008; 10. Yusuf et al 2008; 11.
TRANSCEND Investigators 2008; 12. http://clinicaltrials.gov (NCT00283686); 13. Dahlöf et al. 2002; 14. Dickstein et al. 2002; 15. Pitt et al. 2000; 16.
Brenner et al. 2001; 17. http://clinicaltrials.gov (NCT00090259); 18. http://clinicaltrials.gov (NCT00555217); 19. Pfeffer et al 2003; 20. Papademetriou
et al. 2004; 21. http://clinicaltrials.gov (NCT00120003); 22. Ogihara et al. 2008; 23. http://clinicaltrials.gov (NCT00108706); 24. Laufs et al. 2008; 25.
Suzuki et al. 2005; 26. Massie et al 2008; 27. Lewis et al. 2001; 28. http://clinicaltrials.gov (NCT00249795); 29. http://clinicaltrials.gov (NCT00535925);
30. http://clinicaltrials.gov (NCT00417222); 31. http://clinicaltrials.gov (NCT00454662); 32. http://clinicaltrials.gov (NCT00134160); 33.
http://clinicaltrials.gov (NCT00141453); 34. Schrader et al. 2005
9. ONTARGET
10. PRoFESS
11. TRANSCEND
12. HALT-PKD*
13. LIFE
14. OPTIMAAL
15. ELITE II
16. RENAAL
17. NCT00090259*
*Expected
enrolment
‡Ongoing and completed randomized
controlled trials with death or hard CV
events as or part of the primary
endpoint
¶Valid as of January 2009
Mortality and Morbidity Endpoint Trialsঠwith ARBs
18. VA NEPHRON-D*
19. CHARM
20. SCOPE
21. SCAST*
22. CASE-J
23. ACCOST
24. HIJ-CREATE
25. E-COST
26. I-PRESERVE
Number
of
patients
Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan
Eprosartan
56,631
52,896
24,841 23,940
6,577
1,405
15,693
1
2
5
4
3
7
8
6
9
10
16
12
11
17
18
15
13
14
22
23
25
19
20
34
31
30
32
33
29
28
27
26
24

44. Role of Valsartan as Foundation Therapy
Blood Pressure Control
Primary Prevention
Delaying / preventing
Progression
Reduction of
Morbidity and Mortality

45. Role of Valsartan as Foundation Therapy
Blood Pressure Control
Primary Prevention
Delaying / preventing
Progression
Reduction of
Morbidity and Mortality

46. Neutel et al. Clin Ther 2000;22:961–9
Valsartan: significant reductions in BP from baseline in elderly
patients with hypertension
–19.2*
–8.8
–5.2*
–1.2
0
–5
–10
–15
–20
MSSBP MSDBP
Change
in
BP
from
baseline
to
Week
8
(mmHg)
Valsartan 160 mg‡ (n=73)
Placebo (n=73)
*p<0.001 vs. placebo
‡Patients were randomized to valsartan 80 mg which was then force-titrated to 160 mg after 4 weeks
An 8-week, multicentre, randomized, double-blind, placebo-controlled study in patients ≥65 years with
systolic hypertension
BP: blood pressure; MSDBP: mean sitting diastolic blood pressure; MSSBP: mean sitting systolic blood pressure

47. Valsartan provides 24-hour reductions in ABP similar to amlodipine in
patients with hypertension
Maciejewski et al. Pharmacotherapy 2006;26:889–95
Prospective, randomized, double-blind, crossover comparison ABP study in
African American patients with hypertension
Valsartan 80 or 160 mg¶
Amlodipine 5 or 10 mg¶
¶African American (n=20) patients were randomized to valsartan 80 mg or amlodipine
5 mg once daily for 8–10-weeks; doses could be uptitrated to achieve blood pressure 140/90 mmHg. ABP:
ambulatory blood pressure; SBP: systolic blood pressure
24-hour
mean
1st 4 hours
mean
Daytime
mean
Night-time
mean
Last 8 hours
mean
0
–5
–10
–15
–20
–25
–30
–35
–40
Mean
change
in
SBP
from
baseline
(mmHg)

48. 9 Out of 10 Patients Achieve Goals*
in Less Time with Higher Doses and Combination Therapy
Cumulative
proportion
of
patients
reaching
JNC-7
goals*
(%)
Weir et al. Am J Hypertens 2007;20:811–15
Placebo
(n=1,156)
Valsartan
80 mg
(n=781)
Valsartan HCTZ
80/12.5 mg
(n=96)
Valsartan 160 mg
(n=907)
Valsartan HCTZ
160‡ mg
(n=355)
Valsartan
320 mg
(n=646)
Valsartan HCTZ
320‡ mg
(n=335)
90
80
70
60
50
40
30
20
10
0
Pooled analysis of data from nine randomised, double-blind, placebo-
controlled trials
‡Valsartan at stated dose + HCTZ 12.5 or 25 mg
*<140/90 mmHg

49. Combination
Therapy

50. Which Drug?

51. RAAS
Blockade
CCB
Diuretic

52. For whom should we initiate combination therapy?
Considering initiation with a drug combination
in patients at
high risk or with markedly high baseline BP
2013 ESH/ESC Guidelines for the management of arterial hypertension

53. Average Number of Antihypertensive Agents
Needed Per Patient to Achieve Target SBP Goals
Number of medications
1 2 3 4
Trial (SBP achieved)
Bakris et al. Am J Med 2004;116(5A):30S–8
Dahlof B, et al. Lancet 2005;366:895 –906
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
IDNT (138 mmHg)
RENAAL (141 mmHg)
UKPDS (144 mmHg)
ABCD (132 mmHg)
MDRD (132 mmHg)
HOT (138 mmHg)
AASK (128 mmHg)

57. Rationale for CCB/ARB Therapy
• Notable dual-mechanism therapies
• Complementory mode of action
• CCB induced edema is minimized by ARB
• Wealth of CV outcomes data for Amlodipime and
Valsartan

58. Combination of ARBs and CCBs may
have benefial effects

59. Sinkiewicz et al. Curr Med Res Opin
2009;25:315–24
Amlodipine/valsartan:
significant reductions in BP from baseline in patients with hypertension
compared with Valsartan monotherapy
–14.29*¶
–8.25
–11.47*§
–9.62*
0
–5
–10
–15
–20
MSSBP MSDBP
Change
in
BP
from
baseline
at
Week
8
(mmHg)
Valsartan 160 mg (n=308)
Amlodipine/valsartan 5/160 mg (n=322)
Amlodipine/valsartan 10/160 mg (n=316)
¶p=0.0164 vs. amlodipine/valsartan 5/160 mg; §p=0.0006 vs. amlodipine/valsartan 5/160 mg; *p<0.0001 vs. valsartan; ‡Patients whose
diastolic blood pressure was uncontrolled (≥90 mmHg and <100 mmHg) after a single-blind run-in period with valsartan
An 8-week, multicentre, randomized, double-blind, active-controlled
study in patients with hypertension‡
BP: blood pressure; MSDBP: mean sitting diastolic BP; MSSBP: mean sitting systolic BP
–6.70
–12.18*

60. Schunkert et al. Curr Med Res Opin 2009;25:2655–62
BP: blood pressure; LSM: least squares mean; MSDBP: mean sitting diastolic
blood pressure; MSSBP: mean sitting systolic blood pressure
Amlodipine/valsartan:
significantly greater BP-lowering efficacy from baseline
compared with Amlodipine monotherapy
–12.9
–10.0
–11.4
–9.3
0
–5
–10
–15
MSSBP MSDBP
LSM
change
in
BP
from
baseline
to
Week
8
(mmHg)
Amlodipine/valsartan 10/160 mg (n=472)
Amlodipine 10 mg (n=468)
Difference: –2.87 (95% CI: –4.17,–1.56)
p<0.0001
Difference: –2.11 (95% CI: –2.97,–1.25)
p<0.0001
An 8-week, multicentre, randomized, double-blind study in patients with hypertension randomized to amlodipine/valsartan 10/160 mg
or amlodipine 10 mg after a washout period and 4-week single-blind run-in period with amlodipine 10 mg

61. Amlodipine/valsartan
provides powerful blood pressure reductions across hypertension severities
¶Diastolic blood pressure (DBP) 9099 mmHg, systolic blood pressure (SBP) 140159 mmHg;
‡DBP ≥100 mmHg, SBP ≥160 mmHg
HTN: hypertension; MSSBP: mean sitting systolic blood pressure
1Smith et al. J Clin Hypertens 2007;9:355–64 (Dose 10/160 mg)
2Poldermans et al. Clin Ther 2007;29:279–89 (Dose 5–10/160 mg)
Mild HTN1¶
Mean
change
in
MSSBP
from
baseline
(mmHg)
0
–10
–20
–30
–40
–50
n=69 n=140 n=15
–20
–43
–30
Moderate HTN1‡
Baseline SBP
≥180 mmHg2

62. Role of Valsartan as Foundation Therapy
Blood Pressure Control
Primary Prevention
Delaying / preventing
Progression
Reduction of
Morbidity and Mortality

63. Effective Interventions are Required
Throughout the Cardiovascular Continuum to
Prevent / Delay Disease Progression
MAU: Microalbuminuria
CRP: C-Reactive Protein
LVH: Left Ventricular Hypertrophy
Markers of Disease Progression
↓ CRP ↓ LVH & AF ↓ MAU

64. LVH is an independent risk factor for
reducing survival
LVH: Left Ventricular Hypertrophy
Adapted From: Devereux R, et al. JAMA. 2004;292:2350-2356.

65. Meta-analysis of randomized, controlled trials
of LVH regression in HTN
115:416
.Schmieder RE et al. Am J Med 2003 ; -
16 -
14 -
12 -
10 -
8 -
6 -
4 -
2 -
0
Diuretics
Beta-
blockers
Ca -
antagonist
ACE
inhibitors ARBs
- 8 %
- 6 %
- 11 %
- 10 %
- 13 %
LV mass
reduction
(%)
80 randomized controlled trials
4113 patients

66. Valsartan Reduces
LVH in Previously Untreated Patients with Hypertension
Change
in
LVMI
(g/m
2
)
from
baseline
via
echocardiography
–10**
–21***
Valsartan 80 mg/day ± HCTZ† Atenolol (50 mg/day) ±
HCTZ†
(n=29) (n=29)
**p=0.0082; ***p<0.0001 vs baseline
Randomised, double-blind study: 8 months’ treatment
0
–10
–20
–30
Thürmann PA et al. Circulation 1998;98:2037–42
†If DBP was uncontrolled (>95 mmHg) after 4 weeks of initial therapy, the dose of each agent was doubled;
HCTZ was added after a further 4 weeks if DBP remained uncontrolled
LVH = left ventricular hypertrophy,
LVMI = left ventricular mass index

67. Valsartan based therapy reduces the development of
both new-onset AF and persistent AF in patients with hypertension and high CV risk
Patients 50 years, with treated or untreated hypertension and at high risk of CV events (n=15,245)
Patients
with
AF
(%)
Baseline
AF
New-onset
AF
Persistent
AF
Valsartan-based regimen
Amlodipine-based regimen
Schmieder RE et al. J Hypertens 2008;26:403–11
2.6
2.6
3.7
4.3
1.35
1.97
VALUE = Valsartan Antihypertensive Long-Term Use Evaluation trial, CV = cardiovascular,
AF = atrial fibrillation, OR = odds ratio
p=0.004
p=0.045
“ Novartis is not recommending indications outside the approved BPI in Egypt”

68. Proteinuria is an independent risk factor
for mortality in type 2 diabetes
1.0
0.9
0.8
0.7
0.6
0.5
0 1 2 3 4 5 6 Years
Survival
(all-cause
mortality)
Normoalbuminuria
(n=191)
Microalbuminuria
(n=86)
Macroalbuminuria
(n=51)
Gall, MA et al. Diabetes 1995;44:1303
P<0.01 normo vs. micro- and macroalbuminuria
P<0.05 micro vs. macroalbuminuria

69. Valsartan
80160 mg
Amlodipine
510 mg
Valsartan
80160 mg
Amlodipine
510 mg
Change
from
baseline
in
UAER
at
Week
24
(%)
Patients
(%)
regressing
to
normoalbuminuria
§
(LOCF)
44%*
8%
30%*
15%
Results from a 24-week study in 291 patients# with Type 2 diabetes and microalbuminuria‡ (MARVAL
study)
0
10
20
30
40
50
#Patients completing the study; ‡Median UAER 20200 μg/min; §Defined as UAER <20 μg/min
*p<0.001 vs amlodipine; UAER = urine albumin excretion rate
LOCF = last observation carried forward
35
30
25
20
15
10
5
0
Viberti et al. Circulation 2002;106:672–8
n=146 n=145
n=146 n=145
Valsartan: : 30% of Valsartan-treated Patients
Returned to Normoalbuminuria‡ by Week 24

70. Amano K, et al. International Journal of Cardiology (2012)

71. -47%
-42%
CKD+ CKD-
RR
The primary endpoint was a composite of defined Cardio- or Cerebro-vascular
events such as : stroke, myocardial infarction, heart failure, angina pectoris.
RR= risk reduction to non-ARB treatment, +CKD= patients with chronic kidney diseases , -CKD= patients without
chronic kidney diseases
Amano K, et al. International
Journal of Cardiology (2012)
Valsartan add-on significantly decreased the occurrence of primary endpoint

72. Role of Valsartan as Foundation Therapy
Blood Pressure Control
Primary Prevention
Delaying / preventing
Progression
Reduction of
Morbidity and Mortality

73. Valsartan has a Wealth of Cardiovascular Outcomes Data
1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–906; 3Maggioni et al. Am Heart J 2005;149:548–57;
4Wong et al. J Am Coll Cardiol 2002;40:970–5; 5Cohn et al. N Engl J Med 2001;345:1667–7; 6Hollenberg NK et al. J Hypertens 2007;25:1921–6
VALUE1
15,245 high-risk hypertension patients; Double-blind,
randomized study vs amlodipine
No difference in composite of cardiac mortality and morbidity (primary)
23%  new-onset diabetes
VALIANT2
14,703 post-myocardial infarction (MI) patients; Double-
blind, randomized study vs captopril and vs captopril +
valsartan
No difference vs captopril in all-cause mortality (primary) with better
tolerability
(valsartan is as effective as standard of care)
Val-HeFT3–5
5,010 heart failure (HF) II–IV patients; Double-blind,
randomized study vs placebo
13%  morbidity and mortality (primary)
 left ventricular remodeling
37%  atrial fibrillation occurrence
 HF signs/symptoms
28%  HF hospitalization
DROP6
390 hypertensive patients with Type 2 diabetes and
microalbuminuria, Multicentre, double-blind, randomised,
parallel-group study , to assess the ability of high dosages of
valsartan to have a greater impact on proteinuria reduction
than current approved dosages
51%  Reduction in UAER
13-20% rapid reduction in proteinuria in 1st 4 weeks
In patients that achieved target BP control of <130/80 mmHg, UAER was
reduced up to 66%

74. So you can combine :
valsartan with amlodepine

75. Thank You

76. Thank
You