Transcript Prehypertension To Treat or not to Treat

Unraveling the Mysteries of
Pre-hypertension
Joel Neutel. MD
Professor of Medicine
University of California Irvine
Director of Research
Orange County Research Center
Family History of Hypertension
Age (yr)
Weight (kg)
BMI (kg/m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Neutel JM et al. Am Heart J 1992;124:435-440.
Positive
Negative
44+1.6
83+1.8
27+0.5
127+1.1
77+0.7
44+1.8
83+2.2
27+0.6
127+1.6
77+0.8
Neurohormonal Levels in Normotensive
Patients With and Without a Family History of
Hypertension
310 ± 17
2.1 ± 0.2
2.5
†
300
*
250
190 ± 15
200
150
100
50
0
Family
History
Plasma renin activity
(ng/Ang I/mL/h)
Norepinephrine (pg/mL)
350
No Family
History
*p<0.01.
†p<0.05.
Neutel JM et al. Am Heart J. 1992;124:435-440.
2.0
1.6 ± 0.2
1.5
1.0
0.5
0.0
Family
History
No Family
History
Plasma Insulin Levels and Insulin Sensitivity in Subjects
with and without a Family History of Hypertension
16
*
14.1
0.18
0.16
12
10.8
10
8
6
4
Insulin Sensitivity
Plasma Insulin
14
*
0.157
0.14
0.12
0.1
0.08
0.06
0.04
2
0.02
0
0
Family
History
No Family
History
Neutel JM et al. Am Heart J. 1992;124:435-440.
0.122
Family
History
No Family
History
*P< 0.05
Total Cholesterol and Triglyceride Levels in
Subjects with and without a Family History of
Hypertension
*
217
160
215
140
210
205
200
197
195
Triglyceride Levels
Cholesterol Levels
220
100
80
60
40
20
185
0
No Family
History
Neutel JM et al. Am Heart J. 1992;124:435-440.
112
120
190
Family
History
136
Family
History
No Family
History
*P< 0.05
Left Ventricular Mass Index and Doppler
Echocardio-graphic Characteristics in Normotensive
Subjects With and Without a Family History of
Hypertension
100
90
80
70
Left
60
ventricular
50
mass
40
(g/m2)
30
20
10
0
75 ± 17
*
57 ± 13
Family
History
No Family
History
1.00
0.90
0.80
0.70
0.60
A/E
0.50
ratio
0.40
0.30
0.20
0.10
0
0.64 ± 0.19
†
0.46 ± 0.10
Family
History
No Family
History
*p<0.05.
†p<0.01.
Celentano et al. J Hypertens. 1988;6(suppl 4):107. Graettinger WF et al. Am J Cardiol.
1991;68:51-56.
Proximal and Distal Compliance in Normotensive Subjects With
and Without a Family History of Hypertension
*
1.79 ± 0.38
1.56 ± 0.38
1.8
1.6
0.4 0.34 ± 0.018
1.2
Proximal 1.0
compliance
0.8
(mL/mm Hg)
0.6
Distal
compliance 0.3
(mL/mm Hg)
0.2
0.4
0.1
0.2
*p<0.05.
†p<0.01.
0.50 ± 0.021
0.5
1.4
0.0
†
0.6
Family
History
No Family
History
0.0
Family
History
No Family
History
Family History of Hypertension
Creatinine clearance
(mL/min)
125
*
Albumin excretion ratio
(µg/min)
3.2
120
3.0
115
2.8
110
105
100
2.6
2.4
2.2
95
90
2.0
0
0
Positive
*p<0.01.
Negative
Positive
Negative
Blood Pressure (mm Hg)
WCH in Patients with and without
a Family of Hypertension
WCH (%)
**
Family
History
No Family
History
Neutel J et al., Am Heart J 1992;124:435-
Family
History
No Family
History
** P < 0.01
Characteristics of Normotensives and Hypertensives
With and Without a Family History of Hypertension
NORMOTENSIVE
No Family Family
History
History
(n=29)
(n=40)
HYPERTENSIVE
No
Family
Family
History
History
(n=38)
(n=25)
54.0+2
53.3+1.4
23.8+0.7 28.0+0.5
Age (y)
BMI
(kg/m2)
53.7+1.8
27.3+0.6
53.1+1.6
28.0+0.7
SBP
(mmHg)
DBP
(mmHg)
129+2
129+2
147+2
146+2
79+1
78+1
94+1
94+1
BMI = body mass index
Plasma Norepinephrine and Plasma Renin Activity
**p<0.02
*p<0.05
HT = hypertensive; NT = normotensive
**p<0.02
Neutel J et al., Am Heart J 1992;124:435-448.
*p<0.07
Total Cholesterol Levels in Patients with and without
a Family History of Hypertension
No Family History
Family History
250
**
230
Total
Cholesterol
(mg/dL)
*
**
HT
HT
210
190
170
NT
NT
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
**p<0.002
*p<0.04
Insulin Sensitivity and Plasma Insulin Levels
No Family History
Family History
0.25
0.2
Insulin/Glucose
Ratio
0.15
0.1
0.05
**p<0.01
0
NT
NT
HT
HT
*p<0.02
20
15
Plasma Insulin
(uU/mL)
10
5
**p<0.01
0
NT
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
NT
HT
HT
*p<0.03
Distal Compliance
Distal Compliance (C2) in Patients with and without
a Family History of Hypertension
**
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
*
**p<0.01
*p<0.04
**
Changes in Proximal and Reflective Compliance
**
*
**
NS
*p<0.05
**p<0.01
Neutel JM Am J Cardiol 2006
Endothelial Dysfunction Leads to High Blood
Pressure and Atherosclerotic Disease
NO
Norepinephrine
Hyperinsulinemia Ang II Family History
LDL-cholesterol
Smoking
Dysfunction
Collagen and
SMC migration Lipid deposition and
Fibronectin deposition And growth Inflammatory-cell
infiltrate
Potentiates
High Blood Pressure
Neutel J. 2001
Vasoconstricti
on
clotting
Atherosclerosis
CVD
Changes in Endothelial Function
Dysfunctional Endothelium
Normal Endothelium
AII
NO
NO
AII AII
AIIAII
AII
Patients with Strokes
And Heart Attacks (%)
Renin Activity
Patients with LV
Enlargement (%)
Low
12 (20)
Normal
18 (15)
High
8 (22)
Brunner et al N Eng J Med 1972 ;286: 441
Total
0
Strokes
Heart
Attacks
0
0
14 (11)
8 (6)
6 (5)
5 (14)
4 (11)
2 (6)
Hypertension, Oxidative Stress,
Angiotensin II:
At the Source of Vascular Damage
Adapted from Dzau V, Braunwald E. Am
Heart J. 1991;121:1244-1263.
Regulation of ACEi and NO in Endothelial
Dysfunction and Atherosclerotic Disease
ACEi Therapy
Normal endothelium
AII
NO
Dysfunctional endothelium
AII
NO
NO
NO
NO
AII
AII
AII
ACEi
Monocytes
Platelets
Adapted from Gibbons G. Am J Cardiol, 1997;79, 3-8
Thrombus
Lipid-laden macrophage
Impact of High Normal BP on
CV Disease Risk in Men and Women
Cumulative
incidence (%)
12
WOMEN
10
High normal
8
(140/90)
Prehypertension
Normal
6
4
(130/85)
2
Cumulative
incidence (%)
0
16
14
12
10
8
6
4
2
0
Normal
Optimal
0
2
4
6
Time (y)
8
10
12
(120/80)
MEN
(120/80)
High normal
Normal
Optimal
0
2
4
6
Time (y)
8
10
12
Optimal BP: <120/80 mm Hg; normal BP: 120-129/80-84 mm Hg; high normal: 130-139/85-89 mm Hg.
Vasan RS. N Engl J Med. 2001;345:1291-1297.
MRFIT: Systolic BP And CHD Mortality Risk Pyramid
For Men
SBP (mm Hg)
>180
170-179
160-169
150-159
140-149
130-139
120-129
110-119
<110
% of Total CHD Deaths
7.2
Stage 2
Stage 1
6.8
10.1
19.5
23.4
20.7
Pre-HTN
Normal
9.9
1.3
0.0
Pop. %
RR
0.9
1.2
24.5 2.7 4.6 107
6.2
42.9 12.8 19.0 51
22.8
30.6 28.4 53.2 11
19.0
1.3 6.1 25.1 1
Adapted from Stamler et al. Arch Intern Med 1993;153:596.
JNC 7 Re-Classification of SBP/DBP
JNC VI (1997)
JNC 7 (2003)
Optimal
Normal
< 120 and <80
< 120 and < 80
Normal
< 130 and < 85
Prehypertension
High-normal
120-139 or 80-89
130-139 or 85-89
Stage 1
Stage 1
140-159 or 90-99
140-159 or 90-99
Stage 2
160-179 or 100-109
Stage 2
Stage 3
> 160 or > 100
> 180 or > 110
JNC VI. Arch Intern Med. 1997;157:2413-2446.
JNC 7. JAMA, May 21, 2003-Vol 289, No.19, 2560-2572.
TROPHY
Background and Objectives
Background
 45 million people in the US have prehypertension, a
condition associated with excess cardiovascular risk
 Arteriolar hypertrophy and endothelial dysfunction
contribute to the self-acceleration of this disease. Early
treatment might delay or prevent the development of
hypertension
Objectives
 Determine whether treatment with an ARB in subjects
with prehypertension will:


suppress clinical hypertension during the active treatment
delay the onset of clinical hypertension after discontinuation of
active treatment
Julius, Stevo, et. al. JAMA 2006; 354:1-13
Study Design
TROPHY
Study Design
772 subjects, age > 30 or < 65, never treated for HTN, first visit BP < 160/100,
avg automated BP over 3 visits < 135/85-89 or 130-139 < 89
lifestyle counseling throughout the trial
Candesartan 16 mg qd x 2 years
Placebo x 2 years
(n = 391)
(n = 381)
Placebo x 2 years
Primary Study Endpoints:
• BP > 140 mmHg systolic and / or > 90 mmHg diastolic at any 3 visits
• BP > 160 mmHg systolic and / or > 100 mmHg diastolic at any visit
• BP > 140 mmHg systolic and / or > 90 mm Hg diastolic at last study visit
• In clinical investigator’s judgment pharmacologic therapy is indicated (target
organ damage or other reasons)
Julius, Stevo, et. al. JAMA 2006; 354:1-13
TROPHY STUDY
BP Inclusion Criteria
SBP 130 – 139 mm Hg and
DBP < 89 mm Hg
OR
SBP < 139 mm Hg and
DBP 85 – 89 mm Hg
Julius S. N Engl J Med 2006;354:1-13
TROPHY STUDY
Baseline Characteristics
N
Age (yrs)
Males
Race
White
Black
Other
BMI
Candysartan
391
48.6
231
Placebo
381
48.3
229
312
48
31
29.9
321
31
29
30.0
Julius S. N Engl J Med 2006;354:1-13
TROPHY STUDY
Baseline Characteristics (cont)
BP (mm Hg)
TC (mg/dL)
TRG (mg/dL)
HDL (mg/dL)
Gluc (mg/dL)
Insulin (IU)
Ins/Gluc ratio
Creat (mg/dL)
Candysartan
133.9
202.9
145.8
48.9
95.5
11.7
15.4
0.84
Julius S. N Engl J Med 2006;354:1-13
Placebo
134.1
205.7
159.8
49.2
95.9
11.2
15.1
0.85
TROPHY STUDY
New Onset Hypertension
*
* P<0.001
Julius S. N Engl J Med 2006;354:1-13
4 years
Number of patients
Number of patients
2 years
*
(placebo)
* P<0.007
TROPHY STUDY
Kaplan-Meier Analysis
of New-Onset Clinical Hypertension
Pre-hypertension
SBP 120-139 mmHg or DBP 80-89 mmHg
25 Million Americans have Pre-hypertension
How should this be managed
• Encourage Lifestyle Modifications
• Without compelling indication – no treatment
• With compelling indication – Drug(s) for
compelling indication
JNC 7. JAMA. 2003;289(19):2560-2574
Bothrops jararaca
9
ACE Inhibitors
An ACE inhibitor was first discovered in
snake venom of Bothrops jararaca, a
Brazilian viper
 Identified as a nonapeptide named teprotide
 Also known as bradykinin potentiating
peptide 9 alpha or BBP9 alpha
 Sequence: Pyr-Trp-Pro-Arg-Pro-Gln-IlePro-Pro or PyrWPRPQIPP

8
Proline
H
N
O
OH
proline
ACE Inhibitors

Captopril – first commercial ACE inhibitor.
OH
O
O
N
SH
1-[(2S)-3-Mercapto-2-methyl-1-oxopropyl]-L-proline
10
Lactotripeptides
Clinical trials in Japan demonstrated that
Lactobacillus helveticus and Saccharomyces
cerevisiae fermented milk produced two
tripeptides ile-pro-pro (IPP) and
val-pro-pro (VPP). These tripeptides are well
absorbed from the GI tract when given orally
15
Lactotripeptides
Both IPP and VPP possess ACE
inhibitory activity as determined
by the inhibition of the
metabolism of the test peptide
Hip-His-Leu
15
Changes of SBP (mm Hg)
Antihypertensive effects of VPP and IPP
on spontaneously hypertensive rats
10
0
＊
-10
＊
-20
-30
***
-40
**
*
**
**
* P < 0.05
** P < 0.01
*** P < 0.001
Mean ± SE
**
＊
-50
0
2
4
6
8
10
Time after administration (h)
24
Control
Ile-Pro-Pro (0.3mg/kg)
Val-Pro-Pro (0.6mg/kg)
Fermented Milk (5ml/kg)
(Nakamura et al., J. Dairy Sci. 1995)
Lactotripeptides

AmealPeptide (VPP and IPP) has undergone the most extensive
human clinical and toxicity testing (14 published, randomized,
clinically controlled trials).

No adverse reactions, including cough, have been reported.
AmealPeptide not involved in cytochrome P450-mediated
interactions with other drugs

AmealPeptide exists in two forms: a fermented milk drink (milk is
fermented with Lactobacillus helviticus) and in pill form (derived
by digesting milk casein with a protease from Aspergillus oryzae).

Both the food drink, marketed in Japan as a FOSHU product, and
the pill, marketed in the U.S. as a dietary supplement (with GRAS
recognition from the US FDA), are efficacious in lowering BP.
36
Effect of VPP and IPP on the Conversion of Angiotensin I
to Angiotensin II, and the Bradykinin Production in Aorta
of Spontaneously Hypertensive Rats
Figure 3. Levels of Angiotensin I, Angiotensin II and Bradykinin in aorta were analyzed using
Sep-pak tC18. The peptides in the eluted materials were measured with commercially
available Enzyme Immunoassay kits.
Effects of LTP’s on
Pre-hypertensive Subjects (SBP:120-139mmHg)
150
： Placebo (n=53)
mmHg)
： Treatment (n=53)
Blood pressure (mmHg)
140
SBP
130
*
120
*
*
*
Mean + SD
* P< 0.05
110
100
90
80
DBP
*
70
*
*
60
-4 -2
0
2
4
6
8
10 12 14 16
Time (Week)
Nakamura et al. (J. Nutr. Food, 7:123-137, 2004)
Effects of LTP’s on
Pre-hypertensive Subjects (SBP:120-139 mmHg)
Blood pressure (mmHg)
150
: Placebo (n=20)
Systolic BP
: Treatment (n=20)
140
Mean + SD
* P< 0.05
130
*
*
*
*
*
*
*
8
10 12 14 16
Diastolic BP
90
*
*
80
70
-2
0
2
4
6
Time (Week)
(Sano et al., J. Medical Food)
Effects of LTP’s on
BP in Treated Hypertensive Patients
Systolic Blood Pressure
ΔBP (mmHg)
5
0
-5
-10
-15
-20
ΔBP (mmHg)
5
*
*
*
Placebo (n=13)
(SBP:150.9±9.5, DBP:87.0±9.1 )
Treatment (n=17)
2.6 mg of LTP/100 g fermented milk
(SBP:158.5±11.1, DBP:88.7±9.4 )
0
4
8
12
Diastolic Blood Pressure
0
-5
-10
*
*
8
12
-15
0
Mean + SD * P< 0.05
4
(Week)
Drugs used
Active Placebo
Calcium antagonist
11
9
ß-Blocker
3
4
ACE inhibitor
2
3
Diuretics
4
0
Others
3
3
None
1
3
(Hata et al., Am. J. Clin. Nutr.1996)
Effects of LTP’s on
Stage-1 Hypertensive patients (SBP : 140-159 mmHg)
Blood pressure (mmHg)
： Placebo (n=33)
： Treatment (n=31)
160
SBP
140
* *
120
*
*
*
*
*
*
Mean + SD
* P< 0.01
100
80
* *
-2
0
2
4
6
8
Time (Week)
10 12
Kajimoto et al, (J. Nutr. Food, 5: 55-66, 2002)
2-3: Stratified Analysis of 8 Clinical Trials
by Start Value of Blood Pressure
(Post-hoc analysis; 606 subjects from 8 studies)
Systolic blood pressure (mm Hg)
～160
159～150
149～140 139～130
Diastolic blood pressure (mm Hg)
～100
99～95
94～90
89～85
10.0
0.0
-10.0
*
-20.0
*
-30.0
*
*
*
*
*
Mean + SD
* p<0.05
(3.4-5.4mg/day for 6-12 wks)
Treatment
Placebo
AHEAD STUDY
Achieved Hypertension
Efficacy with
AmealPeptide™ Dietary
Supplement
AHEAD STUDY
A randomized double-blind, placebo
controlled study comparing the efficacy
and safety of AmealPeptide™
Lactotripeptide to placebo in patients
with stage I or stage II hypertension.
Study Schematic
ABPM
2 weeks Single
Blinded Run-in
Phase
ABPM
9 weeks Double Blinded Active Treatment Phase
Randomization
AmealPeptide 15 mg
Placebo
Screening
Week
Visit
-2
R1
-1
R2
0-1d 0
V1 V2
1
V3
3
V4
6
V5
9 9+1d
V6 V7
Patient Demographics and Baseline
Characteristics
Lactotripeptide
15mg
Placebo
30
34
55.3
57.9
Males
17
18
Females
13
16
Caucasian
8
10
Black
3
5
Asian
7
8
Hispanic
11
11
Other
1
0
Weight (kg)
74.6
79.7
BMI (kg.m2)
27.9
29.2
N
Age (yrs)
Gender
Race
Patient Demographics and Baseline
Characteristics (Cont.)
Lactotripeptide
15mg
Placebo
SBP
146.5
145.3
DBP
86.6
83.2
SBP
152.5
150.7
DBP
91.0
88.1
Baseline BP
24-Hour Mean
(mmHg)
Daytime Mean
(mmHg)
Change From Baseline in Mean
Daytime (8am-4pm) BP
Lactotripeptide
Placebo
Change in Mean 24 Hour BP in Patients
With a Mean Daytime BP of > 150 mmHg
at Baseline
Change from baseline in Mean 24
Hour Ambulatory BP in Patients With
a BMI <25 kg/m2
Lactotripeptide
Placebo
Summary of Adverse Events
Lactotripeptide
15mg
Placebo
N
28
32
Total No. of Patients with Adverse
Events
7
9
Cough
0
2
Headache
1
0
Dizziness
1
0
Fatigue
0
0
Muscle Pain
1
0
Dose Response Study
A Prospective, Open-Label, Blinded
End-Point, (PROBE) Parallel Group,
Dose Response Study to Evaluate the
Safety and Efficacy of
AmealPeptide 15mg QD, 50mg QD,
75mg QD, 75mg BID or Placebo in
Patients With Stage I or Stage II
Hypertension
Change from Baseline in Mean Daytime
Systolic BP at Visit 8 as Measured by ABPM
Change in BP (mmHg)
4
Placebo
2.8
2
5mg
15mg
50mg
75mg
75mg BID
0
-0.3
-2
-2.6
-4
-3.4
-6
-8
-6.2
-6.9
*
* P<0.06
Change from Baseline in Mean Daytime
Diastolic BP at Visit 8 as Measured by ABPM
Placebo
5mg
15mg
50mg
75mg
-0.8
-0.9
75mg BID
Change in BP (mmHg)
0
-1
-1.1
-1.5
-2
-2.0
-3
-4
-5
-5.0
-6
100
Time
7:00 AM
6:00 AM
5:00 AM
4:00 AM
3:00 AM
2:00 AM
1:00 AM
12:00 AM
11:00 PM
10:00 PM
9:00 PM
8:00 PM
7:00 PM
6:00 PM
5:00 PM
4:00 PM
3:00 PM
2:00 PM
1:00 PM
12:00 PM
11:00 AM
10:00 AM
9:00 AM
8:00 AM
SBP (mmHg)
24-Hour Systolic BP in Patients
Treated with Lactotripeptide 75mg QD
180
BL
75mg QD
160
140
120
AHEAD II Study
Achieve Hypertension Efficacy with AmealPeptide
Dietary
Supplement – Study II
A Randomized, Double Blind Placebo Controlled
Study Comparing the Efficacy and Safety of
AmealPeptide 75mg BID to Placebo in Patients
With Stage I or Stage II Hypertension
Overall Study Design and Study Rationale
3-4 weeks Single Blinded
Run-in Phase
6 weeks Double Blinded Treatment Phase
Randomization
Placebo
AmealPeptide 75 mg BID
Screening
Week
Visit
-3
1
-2
2
-1
3
0-1d 0
4* 4A
2
5
4
6
6 6+1d
7 7A
Patient Demographics and
Baseline Characteristics
Figure 2. Mean Change in Daytime
(8am-4pm) Systolic BP
Placebo
LTP 75mg BID
0.0
-3.6
*
* P<0.01
Casein hydrolysate containing Val-Pro-Pro and Ile-Pro-Pro improves central
blood pressure and arterial stiffness in stage-I hypertensive subjects:
A randomized, double-blind, placebo-controlled trial
Introduction
• Recently, many clinical trials such as ASCOT-CAFE study suggest that
central BP independently predicts future CV events and correlates more
closely with CV events than brachial BP.
• Similarly, a large number of publications have demonstrated that arterial
stiffness (PWV: pulse wave velocity) has an independent predictive values
for CV events.
• There was no data that VPP and IPP reduced central BP or PWV.
Methods
• Design: A randomized, double-blind, placebo-controlled trial
• Subjects: 70 Japanese subjects with untreated stage-I hypertention
• Test sample: Active (VPP+IPP=3.4mg/day) or placebo tablets
• Intervention period: 8 weeks
• Evaluation: Central BP, PWV
Nakamura et al. Atherosclerosis 2011
Results
ba-PWV
Change in BP (mm Hg)
Baseline
Change
139.4±4.5
-11.0±11.0
0
-5
-10
-15
-20
-25
139.1±5.0
-4.5±9.6
**
***
Active
‡
Placebo
Change in PWV (cm/sec)
Central SBP (SphygmoCor)
1604.2±194.3
-73.9±130.0
1582.7±191.6
-8.4±137.1
0
-50
-100
**
-150
-200
-250
Active
†
Placebo
Values are mean ± SD. **P<0.01, ***P<0.001 for change from baseline (paired t-test).
†P<0.05, ‡P<0.01 vs placebo (unpaired t-test).
Conclusion
It was confirmed that an 8-week intervention with VPP and IPP significantly
improved central BP and PWV. These results suggest that consecutive
intake of VPP and IPP might have beneficial effects on arterial properties
and CV event prevention.
Nakamura et al. Atherosclerosis 2011
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
2 mm Hg
decrease in
mean SBP
Lewington S et al. Lancet 2002;360:1903-1913.
7% reduction in
risk of ischemic
heart disease
mortality
10% reduction in
risk of stroke
mortality
Prevention Prevention Prevention
“You can’t help
getting older but you
don’t have to get old.”
George Burns
1896 – 1996
41