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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