unraveling the mysteries of pre-hypertension
DESCRIPTION
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. Neutel JM et al. Am Heart J 1992;124:435-440. 350. 2.5. 300. 2.0. 250. 1.5. 200. - PowerPoint PPT PresentationTRANSCRIPT
Unraveling the Mysteries of Pre-hypertension
Joel Neutel. MDProfessor of MedicineUniversity of California IrvineDirector of ResearchOrange County Research Center
Family History of HypertensionPositive Negative
Age (yr) 44+1.6 44+1.8
Weight (kg) 83+1.8 83+2.2
BMI (kg/m2) 27+0.5 27+0.6
Systolic BP (mmHg) 127+1.1 127+1.6
Diastolic BP (mmHg) 77+0.7 77+0.8
Neutel JM et al. Am Heart J 1992;124:435-440.
Neurohormonal Levels in Normotensive Neurohormonal Levels in Normotensive Patients With and Without a Family History of Patients With and Without a Family History of
HypertensionHypertension
Nor
epin
ephr
ine
(pg/
mL)
*p<0.01.†p<0.05.Neutel JM et al. Am Heart J. 1992;124:435-440.
Pla
sma
reni
n ac
tivity
(ng
/Ang
I/m
L/h)
0
50
100
150
200
250
300
350
0.0
0.5
1.0
1.5
2.0
2.5
FamilyHistory
No FamilyHistory
FamilyHistory
No FamilyHistory
310 ± 17
190 ± 15**
2.1 ± 0.2
1.6 ± 0.2
††
Plasma Insulin Levels and Insulin Sensitivity in Subjects with and without a Family History of Hypertension
14.1
10.8
0
2
4
6
8
10
12
14
16
0.122
0.157
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
Pla
sma
Insu
lin
Insu
lin
Sen
siti
vity
* *
*P< 0.05Neutel JM et al. Am Heart J. 1992;124:435-440.
Family History
No Family History
Family History
No Family History
Total Cholesterol and Triglyceride Levels in Subjects with and without a Family History of
Hypertension
217
197
185
190
195
200
205
210
215
220
136
112
0
20
40
60
80
100
120
140
160
Cho
lest
erol
Lev
els
Tri
glyc
erid
e L
evel
s
*
*P< 0.05Neutel JM et al. Am Heart J. 1992;124:435-440.
Family History
No Family History
Family History
No Family History
Left Ventricular Mass Index and Doppler Left Ventricular Mass Index and Doppler Echocardio-graphic Characteristics in Normotensive Echocardio-graphic Characteristics in Normotensive
Subjects With and Without a Family History of Subjects With and Without a Family History of HypertensionHypertension
Leftventricular
mass(g/m2)
FamilyHistory
No FamilyHistory
A/Eratio
0
10
20
30
4050
60
70
80
90100 75 ± 17
57 ± 13
0
0.10
0.20
0.30
0.400.50
0.60
0.70
0.80
0.901.00
0.64 ± 0.19
0.46 ± 0.10
FamilyHistory
No FamilyHistory
**††
*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.
1.56 ± 0.38
1.79 ± 0.38
Proximal and Distal Compliance in Normotensive Subjects With Proximal and Distal Compliance in Normotensive Subjects With and Without a Family History of Hypertensionand Without a Family History of Hypertension
Proximalcompliance(mL/mm Hg)
*p<0.05.†p<0.01.
FamilyHistory
No FamilyHistory
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.34 ± 0.018
0.50 ± 0.021
Distalcompliance(mL/mm Hg)
**
FamilyHistory
No FamilyHistory
††
Family History of HypertensionFamily History of HypertensionCreatinine clearance
(mL/min)Albumin excretion ratio
(µg/min)
125
120
115
110
105
100
95
90
0Positive Negative
*p<0.01.
Positive Negative
3.2
3.0
2.8
2.6
2.4
2.2
2.0
0
*
WCH in Patients with and without a Family of Hypertension
Blo
od P
ress
ure
(m
m H
g)
WC
H
(%)
**
** P < 0.01Neutel J et al., Am Heart J 1992;124:435-448.
FamilyHistory
No FamilyHistory
No FamilyHistory
FamilyHistory
Characteristics of Normotensives and HypertensivesWith and Without a Family History of Hypertension
NORMOTENSIVE HYPERTENSIVE
No Family History
(n=29)
Family History
(n=40)
No Family History
(n=25)
Family History
(n=38)
Age (y) 53.7+1.8 53.1+1.6 54.0+2 53.3+1.4
BMI (kg/m2)
27.3+0.6 28.0+0.7 23.8+0.7 28.0+0.5
SBP (mmHg)
129+2 129+2 147+2 146+2
DBP (mmHg)
79+1 78+1 94+1 94+1
BMI = body mass index
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
**p<0.02
*p<0.05
**p<0.02
*p<0.07
Plasma Norepinephrine and Plasma Renin Activity
170
190
210
230
250
NT NT HT HT
Total Cholesterol
(mg/dL)
No Family History
Family History
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
**p<0.002
*p<0.04
** ***
Total Cholesterol Levels in Patients with and without
a Family History of Hypertension
0
5
10
15
20
NT NT HT HT
Plasma Insulin
(uU/mL)
0
0.05
0.1
0.15
0.2
0.25
NT NT HT HT
Insulin/Glucose Ratio
No Family History
Family History
**p<0.01
*p<0.03
**p<0.01
*p<0.02
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
Insulin Sensitivity and Plasma Insulin Levels
HT = hypertensive; NT = normotensive
Neutel J et al., Am Heart J 1992;124:435-448.
**p<0.01
*p<0.04
** ***
Distal Compliance (C2) in Patients with and without
a Family History of Hypertension
Dis
tal C
ompl
ianc
e
**
*
**
NS
*p<0.05
**p<0.01
Changes in Proximal and Reflective Compliance
Neutel JM Am J Cardiol 2006
Endothelial Dysfunction Leads to High Blood Pressure and Atherosclerotic Disease
LDL-cholesterolHyperinsulinemia Family History
DysfunctionDysfunctionDysfunctionDysfunction
Vasoconstriction
Lipid deposition andInflammatory-cell
infiltrate
Ang IINorepinephrine
Smoking
NO
Collagen and
Fibronectin deposition
SMC migration
And growth clotting
High Blood Pressure Atherosclerosis
CVD
Potentiates
Potentiates
Neutel J. 2001
Normal Endothelium
NOAIINO
AII
Dysfunctional Endothelium
AII
Changes in Endothelial Function
AII AIIAII
Patients with StrokesAnd Heart Attacks (%)
Patients with LV HeartRenin Activity Enlargement (%) Total Strokes Attacks
Low
Normal
High
12 (20)
18 (15)
8 (22)
0
14 (11)
5 (14)
0
8 (6)
4 (11)
0
6 (5)
2 (6)
Brunner et al N Eng J Med 1972 ;286: 441
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
Lipid-laden macrophage
ThrombusMonocytes
Platelets
AII AII
NO NO
ACEi
Normal endothelium Dysfunctional endothelium
Adapted from Gibbons G. Am J Cardiol, 1997;79, 3-8
NO AII AII AII
NO NO
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.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.
Cu
mu
lati
ve
inci
den
ce (
%)
Cu
mu
lati
ve
inci
den
ce (
%) 1616
12121010
8866442200
1414
00 22 44 66 88 1010 1212Time (y)Time (y)
OptimalOptimal
NormalNormal
High normalHigh normal
Impact of High Normal BP on CV Disease Risk in Men and Women
Impact of High Normal BP on CV Disease Risk in Men and Women
1212
1010
88
66
44
22
0000 22 44 66 88 1010 1212
Time (y)Time (y)
OptimalOptimal
NormalNormal
High normalHigh normal
Cu
mu
lati
ve
inci
den
ce (
%)
Cu
mu
lati
ve
inci
den
ce (
%) WOMEN
MEN
(140/90)
(130/85)
(120/80)
Prehypertension
Normal
(120/80)
SBP (mm Hg) % of Total CHD Deaths Pop. % RR
>180 7.2 0.9170-179 6.8 1.2160-169 10.1 2.7150-159 19.5 6.2140-149 23.4 12.8130-139 20.7 22.8120-129 9.9 28.4110-119 1.3 19.0<110 0.0 6.1
MRFIT: Systolic BP And CHD Mortality Risk Pyramid For Men
Stage 1 42.9 19.0 51
Adapted from Stamler et al. Arch Intern Med 1993;153:596.
Stage 2 24.5 4.6 107
Pre-HTN 30.6 53.2 11 Normal 1.3 25.1 1
JNC VI (1997)JNC VI (1997) JNC 7 (2003)JNC 7 (2003)
OptimalOptimal
< 120 and <80< 120 and <80
NormalNormal
< 120 and < 80< 120 and < 80
NormalNormal
< 130 and < 85< 130 and < 85PrehypertensionPrehypertension
120-139 or 80-89120-139 or 80-89High-normalHigh-normal
130-139 or 85-89130-139 or 85-89
Stage 1Stage 1
140-159 or 90-99140-159 or 90-99
Stage 1Stage 1
140-159 or 90-99140-159 or 90-99
Stage 2Stage 2
160-179 or 100-109160-179 or 100-109 Stage 2 Stage 2
>> 160 or 160 or >> 100 100Stage 3Stage 3
>> 180 or 180 or >> 110 110
JNC 7 Re-Classification of SBP/DBPJNC 7 Re-Classification of SBP/DBP
JNC VI.JNC VI. Arch Intern Med. Arch Intern Med. 1997;157:2413 1997;157:2413-2-2446.446.JNC 7. JNC 7. JAMAJAMA, May 21, 2003-Vol 289, No.19, 2560-2572., May 21, 2003-Vol 289, No.19, 2560-2572.
Hyp
erte
nsio
nH
yper
tens
ion
Julius, Stevo, et. al. JAMA 2006; 354:1-13
TROPHY TROPHY
Background and ObjectivesBackground and Objectives
BackgroundBackground 45 million people in the US have prehypertension, a 45 million people in the US have prehypertension, a
condition associated with excess cardiovascular riskcondition associated with excess cardiovascular risk Arteriolar hypertrophy and endothelial dysfunction Arteriolar hypertrophy and endothelial dysfunction
contribute to the self-acceleration of this disease. Early contribute to the self-acceleration of this disease. Early treatment might delay or prevent the development of treatment might delay or prevent the development of hypertensionhypertension
ObjectivesObjectives Determine whether treatment with an ARB in subjects Determine whether treatment with an ARB in subjects
with prehypertension will:with prehypertension will: suppress clinical hypertension during the active treatmentsuppress clinical hypertension during the active treatment delay the onset of clinical hypertension after discontinuation of delay the onset of clinical hypertension after discontinuation of
active treatmentactive treatment
Study DesignStudy Design
TROPHYTROPHY
Study DesignStudy Design
772 subjects, age 772 subjects, age >> 30 or 30 or << 65, never treated for HTN, first visit BP < 160/100, 65, never treated for HTN, first visit BP < 160/100, avg automated BP over 3 visits avg automated BP over 3 visits << 135/85-89 or 130-139 135/85-89 or 130-139 << 89 89
Candesartan 16 mg qd x 2 yearsCandesartan 16 mg qd x 2 years(n = 391)(n = 391)
Placebo x 2 yearsPlacebo x 2 years
Primary Study Endpoints:Primary Study Endpoints: • BP BP >> 140 mmHg systolic and / or 140 mmHg systolic and / or >> 90 mmHg diastolic at any 3 visits 90 mmHg diastolic at any 3 visits • BP BP >> 160 mmHg systolic and / or 160 mmHg systolic and / or >> 100 mmHg diastolic at any visit 100 mmHg diastolic at any visit• BP BP >> 140 mmHg systolic and / or 140 mmHg systolic and / or >> 90 mm Hg diastolic at last study visit 90 mm Hg diastolic at last study visit• In clinical investigator’s judgment pharmacologic therapy is indicated (target In clinical investigator’s judgment pharmacologic therapy is indicated (target organ damage or other reasons)organ damage or other reasons)
Placebo x 2 yearsPlacebo x 2 years(n = 381)(n = 381)
lifestyle counseling throughout the triallifestyle counseling throughout the trial
Julius, Stevo, et. al. JAMA 2006; 354:1-13
TROPHY STUDYBP 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 STUDYBaseline Characteristics
Candysartan Placebo
N 391 381
Age (yrs) 48.6 48.3
Males 231 229
Race
White 312 321
Black 48 31
Other 31 29
BMI 29.9 30.0
Julius S. N Engl J Med 2006;354:1-13
TROPHY STUDYBaseline Characteristics (cont)
Candysartan Placebo
BP (mm Hg) 133.9 134.1
TC (mg/dL) 202.9 205.7
TRG (mg/dL) 145.8 159.8
HDL (mg/dL) 48.9 49.2
Gluc (mg/dL) 95.5 95.9
Insulin (IU) 11.7 11.2
Ins/Gluc ratio 15.4 15.1
Creat (mg/dL) 0.84 0.85
Julius S. N Engl J Med 2006;354:1-13
TROPHY STUDYNew Onset Hypertension
*
* P<0.007
*
* P<0.001
2 years 4 years
(placebo)
Julius S. N Engl J Med 2006;354:1-13
Num
ber
of p
atie
nts
Num
ber
of p
atie
nts
TROPHY STUDYTROPHY STUDYKaplan-Meier Analysis Kaplan-Meier Analysis
of New-Onset Clinical Hypertensionof New-Onset Clinical Hypertension
Pre-hypertensionSBP 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
8
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-Ile-
Pro-Pro or PyrWPRPQIPP
Proline
HN O
OHproline
ACE Inhibitors
10
N
OOH
O
SH
1-[(2S)-3-Mercapto-2-methyl-1-oxopropyl]-L-proline
Captopril – first commercial ACE inhibitor.
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 orally15
Lactotripeptides
Both IPP and VPP possess ACE
inhibitory activity as determined
by the inhibition of the
metabolism of the test peptide
Hip-His-Leu15
Fermented Milk (5ml/kg)Val-Pro-Pro (0.6mg/kg)
Ile-Pro-Pro (0.3mg/kg)Control
-50
-40
-30
-20
-10
0
10
0 2 4 6 8 10 24
****
**
**
**
*
***
P < 0.05
P < 0.01
P < 0.001
Ch
an
ges o
f S
BP
(m
m H
g)
Time after administration (h)
Mean ± SE
(Nakamura et al., J. Dairy Sci. 1995)
Antihypertensive effects of VPP and IPP on spontaneously hypertensive rats
*
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.
60
70
80
90
100
110
120
130
140
150
-4 -2 0 2 4 6 8 10 12 14 16
: Placebo (n=53) : Treatment (n=53)
SBP
DBP
Time (Week)
Blo
od p
ress
ure
(m
mH
g)
* * * *
* * *
Nakamura et al. (J. Nutr. Food, 7:123-137, 2004)
Effects of LTP’s onPre-hypertensive Subjects (SBP:120-139mmHg)
mmHg)
P< 0.05Mean + SD
130
140
150
70
80
90
-2 0 2 4 6 8 10 12 14 16
Systolic BP
Diastolic BP
Time (Week)
Blo
od p
ress
ure
(mm
Hg)
* * * ** *
* * *
: Placebo (n=20)
: Treatment (n=20)
(Sano et al., J. Medical Food)
P< 0.05Mean + SD
Effects of LTP’s onPre-hypertensive Subjects (SBP:120-139 mmHg)
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 )
12 P< 0.05
-20-15-10-505
ΔB
P (
mm
Hg)
0 4 8 12
Systolic Blood Pressure
-15
-10
-5
0
5
ΔB
P (
mm
Hg)
0 4 8
Diastolic Blood Pressure
(Hata et al., Am. J. Clin. Nutr.1996)
Effects of LTP’s onBP in Treated Hypertensive Patients
(Week)Mean + SD
Drugs used Active PlaceboCalcium antagonist 11 9ß-Blocker 3 4ACE inhibitor 2 3Diuretics 4 0Others 3 3None 1 3
Drugs used Active PlaceboCalcium antagonist 11 9ß-Blocker 3 4ACE inhibitor 2 3Diuretics 4 0Others 3 3None 1 3
Blo
od p
ress
ure
(mm
Hg)
80
100
120
140
160
0-2 2 4 6 8 10 12
: Placebo (n=33) : Treatment (n=31)
SBP
Time (Week)
Kajimoto et al, (J. Nutr. Food, 5: 55-66, 2002)
Effects of LTP’s onStage-1 Hypertensive patients (SBP : 140-159 mmHg)
P< 0.01Mean + SD
(Post-hoc analysis; 606 subjects from 8 studies)
-30.0
-20.0
-10.0
0.0
10.0~ 160 159 ~ 150 149 ~ 140 139 ~ 130 ~ 100 99 ~ 95 94 ~ 90 89 ~ 85
Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)
TreatmentPlacebo
2-3: Stratified Analysis of 8 Clinical Trials by Start Value of Blood Pressure
(3.4-5.4mg/day for 6-12 wks)
* * * *
* * *
p<0.05Mean + SD
AHEAD STUDYAHEAD STUDY
Achieved Hypertension
Efficacy with
AmealPeptide™ Dietary
Supplement
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.
AHEAD STUDYAHEAD STUDY
2 weeks Single
Blinded Run-in Phase
9 weeks Double Blinded Active Treatment Phase
Randomization AmealPeptide 15 mg Placebo Screening Week -2 -1 0-1d 0 1 3 6 9 9+1d Visit R1 R2 V1 V2 V3 V4 V5 V6 V7
Study SchematicABPM ABPM
Lactotripeptide
15mg
Placebo
N 30 34
Age (yrs) 55.3 57.9
Gender
Males 17 18
Females 13 16
Race
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
Patient Demographics and Baseline Characteristics
Lactotripeptide
15mg
Placebo
Baseline BP
24-Hour Mean (mmHg)
SBP 146.5 145.3
DBP 86.6 83.2
Daytime Mean (mmHg)
SBP 152.5 150.7
DBP 91.0 88.1
Patient Demographics and Baseline Characteristics (Cont.)
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
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
Summary of Adverse Events
Dose Response StudyDose Response Study
A Prospective, Open-Label, A Prospective, Open-Label, Blinded End-Point, (PROBE) Blinded End-Point, (PROBE)
Parallel Group, Dose Response Parallel Group, Dose Response Study to Evaluate the Safety Study to Evaluate the Safety
and Efficacy of and Efficacy of AmealPeptide 15mg QD, 50mg AmealPeptide 15mg QD, 50mg
QD, 75mg QD, 75mg BID or QD, 75mg QD, 75mg BID or Placebo in Patients With Stage Placebo in Patients With Stage
I or Stage II HypertensionI or Stage II Hypertension
Change from Baseline in Mean Daytime Change from Baseline in Mean Daytime Systolic BP at Visit 8 as Measured by ABPMSystolic BP at Visit 8 as Measured by ABPM
-8
-6
-4
-2
0
2
4 Placebo
5mg 15mg 50mg 75mg 75mg BID
Ch
ang
e in
BP
(m
mH
g)
2.8
-6.9
-0.3
-3.4
-6.2
-2.6
*
* P<0.06
Change from Baseline in Mean Daytime Change from Baseline in Mean Daytime Diastolic BP at Visit 8 as Measured by ABPMDiastolic BP at Visit 8 as Measured by ABPM
-6
-5
-4
-3
-2
-1
0Placebo 5mg 15mg 50mg 75mg 75mg BID
Ch
ang
e in
BP
(m
mH
g)
-1.1
-5.0
-1.5
-0.8 -0.9
-2.0
24-Hour Systolic BP in Patients 24-Hour Systolic BP in Patients Treated with Lactotripeptide 75mg QDTreated with Lactotripeptide 75mg QD
100
120
140
160
1808:
00 A
M
9:00
AM
10:0
0 A
M
11:0
0 A
M
12:0
0 PM
1:00
PM
2:00
PM
3:00
PM
4:00
PM
5:00
PM
6:00
PM
7:00
PM
8:00
PM
9:00
PM
10:0
0 PM
11:0
0 PM
12:0
0 A
M
1:00
AM
2:00
AM
3:00
AM
4:00
AM
5:00
AM
6:00
AM
7:00
AM
BL
75mg QD
Time
SB
P (
mm
Hg
)
AHEAD II StudyAHEAD II StudyAAchieve chieve HHypertension ypertension EEfficacy with fficacy with
AAmealPeptide mealPeptide DDietary ietary Supplement – Study Supplement – Study IIII
A Randomized, Double Blind Placebo A Randomized, Double Blind Placebo Controlled Study Comparing the Efficacy and Controlled Study Comparing the Efficacy and Safety of AmealPeptide 75mg BID to Placebo Safety of AmealPeptide 75mg BID to Placebo
in Patients With Stage I or Stage II in Patients With Stage I or Stage II HypertensionHypertension
Overall Study Design and Study Overall Study Design and Study RationaleRationale
3-4 weeks Single Blinded
Run-in Phase 6 weeks Double Blinded Treatment Phase
Randomization Placebo AmealPeptide 75 mg BID Screening Week -3 -2 -1 0-1d 0 2 4 6 6+1d Visit 1 2 3 4* 4A 5 6 7 7A
Patient Demographics and Patient Demographics and Baseline CharacteristicsBaseline Characteristics
Figure 2. Mean Change in Figure 2. Mean Change in Daytime (8am-4pm) Daytime (8am-4pm)
Systolic BPSystolic BP
0.0
-3.6
Placebo LTP 75mg BID
* P<0.01
*
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
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
Central SBP (SphygmoCor)
-25-20-15-10-50
Active Placebo
139.4±4.5-11.0±11.0
139.1±5.0-4.5±9.6
***
**
ba-PWV
-250
-200
-150
-100
-50
0
Active Placebo
Cha
nge
in P
WV
(cm
/sec
)
1604.2±194.3-73.9±130.0
1582.7±191.6-8.4±137.1
**
BaselineChange
Cha
nge
in B
P (
mm
Hg)
Results
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
Nakamura et al. Atherosclerosis 2011
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.
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
Prevention Prevention Prevention
“You can’t help getting older but you don’t have to get old.”
George Burns
1896 – 1996
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