obesity related hypertension · pai-1 release: differing effects of aceinhibition vs at 1 receptor...

OBESITY RELATED HYPERTENSION

By

Mohie-Aldien Elsayed (MD)

Obesity Stone relief from the tomb of the nobleman

Mereruka at Saqqara, Egypt (c. 2350 B.C.),

showing Mereruka

in a boat, being fed by one of his servants

Ancient Egyptian writer

(Egyptian museum-Cairo)

Genetic

Neurologic and

Physiologic

Biochemical

Environmental Cultural and

Socio-economic

1. Adapted from Weighing the Options; 1995:52. 2. Clinical guidelines. National Heart, Lung, and Blood Institute

Web site. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm. Accessed March, 2001.

Aetiology of obesity: numerous complex and inter-related factors

Trends in Adult Obesity

Note: Data are for ages 20 years and over, age adjusted to the 2000 standard population. Obesity is defined as BMI >= 30.0.

Source: National Health Examination Survey, National Health and Nutrition Examination Surveys I, II, III and 1999-2000, NCHS, CDC.

0

10

20

30

40

0

10

20

30

40

Percent

Males

Females

1960-62 1971-74 1976-80 1988-94 1999-2000

Percent

Total

Prevalence = the total

number of cases of the

risk factor in the

population at a given time

Incidence: is a measure

of the risk of developing

some new condition

within a specified period

of time

21.129

36 37.9

23.1 26.2

17.624.4

29 27 26.3 29.435.2 32.332.7

59.8

4.3

16

12.4

32.1

5.5

14

2.4

8.3

1624

16

31.4

32.3 40.6

0

20

40

60

80

M F M F M F M F M F M F M F M F

Pe

rce

nta

ge

Obesity Patterns Among Adults in N Africa /Middle East

Jordan

1994-96

GNP 1150

BMI>30

25<BMI<30

Morocco

1998-99

GNP 1240

Egypt

1998

GNP 1290

Tunisia

1990

GNP 2060

Saudi Arabia

1996

GNP 6910

M Male

F Female

Iran

1999

GNP 1650

Bahrain

1991-92

Kuwait

1993-94

Source: Popkin (2002). Pub. Health Nutr 5: 93-103.

Waist Circumference Cut-off Points for Abdominal Obesity recommended

by IDF and WHO in Different Ethnic Groups

* Cut-off points to be used until more specific data are available

Assessment of Overweight and Obesity

• Waist Circumference

–High risk:

• Men >102 cm (40 in)

• Women >88 cm (35 in)

•Body Mass Index (BMI): weight (lbs) X 703

height (inches2)

– Overweight = 25 - 29.9 kg/m2

– Obesity = > 30 kg/m2

Abdominal obesity and waist

circumference thresholds • New IDF criteria:

NCEP 2002; International Diabetes Federation (2005)

Current NCEP ATP-III criteria

>102 cm (>40 in) in men, >88 cm (>35 in) in women

Men Women

Europid >94 cm (37.0 in) >80 cm (31.5 in)

South Asian >90 cm (35.4 in) >80 cm (31.5 in)

Chinese >90 cm (35.4 in) >80 cm (31.5 in)

Japanese >85 cm (33.5 in) >90 cm (35.4 in)

Abdominal obesity and increased risk of

cardiovascular events

Dagenais et al 2005

Ad

jus

ted

rela

tive

ris

k

1 1 1

1.17 1.16 1.14

1.29 1.27

1.35

0.8

1

1.2

1.4

CVD death MI All-cause deaths

Tertile 1

Tertile 2 Tertile 3

Men Women <95

95–103 >103

<87

87–98 >98

Waist

circ. (cm):

Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-C, total-C

The HOPE Study

Adverse cardiometabolic effects of products

of adipocytes

Adipose

tissue

↑ IL-6

↓ Adiponectin

↑ Leptin

↑ TNFα

↑ Adipsin

(Complement D)

↑ Plasminogen

activator inhibitor-1

(PAI-1)

↑ Resistin

↑ FFA

↑ Insulin

↑ Angiotensinogen

↑ Lipoprotein lipase

↑ Lactate

Inflammation

Type

2 diabetes

Hypertension

Atherogenic

dyslipidaemia

Thrombosis Atherosclerosis

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

Visceral fat Subcutaneous fat

Intraperitoneal: omental, mesenteric, and umbilical

Extraperitoneal: peri-pancreatic , peri-renal Intra-pelvic:

gonadal (epidydimal) & uro-genital

Truncal Gluteo-femoral Mammary Inguinal

(reported in animal studies)

M: 20% & W: 5-10% of total body fat M: 80% & W: 90% of total body fat

Large less differentiated active adipocyte Small differentiated less active adipocyte

Secrete: adiponectin , Visfatin, PAI-1, IL-6

Angiotensinogen ,,TNF- , leptin, , resistin,

Secrete: TNF- , leptin, adiponectin

Sensitive to: AngII, catecholamines, cytokines

glucocorticoid ,androgen PPAR&PAI-1

Sensitive to: insulin,Pgs, Leptin,

Adiponectin

High lipolysis FFA in portal (direct access)

& systemic circulation

Less (Higher storage)

High risk of:

- Insulin resistance - Hyperinsulinemia

- Hypercholesterolemia - Low HDL cholesterol

- Diabetes mellitus - Coronary artery disease

- Hypertension - Stroke

No known health risks

Frayn 2002; Caballero 2003; Misra & Vikram 2003

Visceral Vs Subcutaneous Fat

Small,dense

LDL-C Low HDL-C

Hepatic Insulin

resistance

hepatic glucose output

TG-rich VLDL-C

CETP,lipolysis

FFA

Lipolysis

Long-term b-cells damage & insulin secretion

Short-term stimulation of insulin secretion

Mesenchymal

precursor

Endothelial dysfunction Inflammation Atherogenic dyslipidaemia Thrombosis

Hypertension CORONARY ARTERY DISEAS Type 2 diabetes

Ang II(-)

Insulin resistant

Low proliferation &

differentiation capacity

Intra-abdominal adiposity

Large insulin resistance

adipocyte

Preadipocyte Insulin

sensitive

High proliferation &

differentiation capacity

Small insulin sensitive

adipocyte

Low fat

infiltration

Adiponectin

(+)

Glucose utilisation

Insulin sensitivity

Agiotensinogen, PAI-

1,IL-6 , TNF , Resistin Leptin

& Adiponectin

Stroke

Coronary

heart

disease

Cancer (endometrial, breast, colon)

Diabetes

THE PROBLEMS

20 Years Ago

210 Calories

2.4 ounces

Today

610 Calories

6.9 ounces

How to burn* 400 calories:

Walk 2 hr 20 Minutes Low HDL

Insulin

Resistance

CARDIOMETABOLIC

Syndrome

High LDL

Hypertension

Endothelial Dysfunction

Mortality

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

• Risk of Mortality

The Problems to be solved :

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

• Risk of Mortality

The Problems to be solved :

Obesity related hypertension Pathogenesis

NHANES III Odds Ratio for Hypertension* According to Sex, Age, and BMI

*Defined as mean systolic blood pressure 140 mm Hg, mean diastolic 90 mm Hg, or currently taking antihypertensive medication.

Brown C et al Body Mass Index and the Prevalence of Hypertension and Dyslipidemia. Obes Res. 2000; 8:605-619.

Women

1 1 1 1.4 2.4

1.4 2

3.3

1.3

7 5.9

1.9

0 1 2 3 4 5 6 7 8 9

10

20-39 40-59 60+

BMI <25 BMI 25-<27 BMI 27-<30 BMI >-30

Men

1 1 1

2.3 1.5 1.2

3.1 1.9

0.9

7.8

4.5

1.6

0 1 2 3 4 5 6 7 8 9

10

20-39 40-59 60+

BMI <25 BMI 25-<27 BMI 27-<30 BMI >30

J.Hyp (2001),19,669-674

Decrease risk of diabetes

ARBs Efficacy in Obese Hypertensive Patients

-8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8

Diastolic BP

Overall (N = 1,191)

Obese (n = 650)

Not obese (n = 537)

Systolic BP

Overall (N = 1,191)

Obese (n = 650)

Not obese (n = 537)

Trough change from baseline at Wk 8, ITT

Favors Candesartan Favors Losartan

14

Obese = BMI ≥ 30 kg/m2.

†Post hoc. ITT population. Meta-analysis CLAIM project

Asmar R and Nisse-Durgast S,Vasc.Health and Risk Management,2006,2(3),317-323

(n = 3013 elderly hypertensives resistant to monotherapy , overweight(BMI 26.6±4.2 kg/m2)

4weeks(8 mg candesartan)

8weeks(16 mg candesartan)

<140/90 mm Hg

Perc

enta

ge o

f patients

with n

orm

alized B

p 100

90

80

70

60

50

40

30

20

10

0

43%

65.5%

A large scale study of Ang II inhibition in an elderly

resistant hypertensives

(CHANCE study)

Asmar R and Nisse-Durgast S,Vasc.Health and Risk Management,2006,2(3),317-323

A large scale study of AngII inhibition in an elderly

resistant hypertensives (CHANCE study)

(n = 3013 elderly hypertensives resistant to monotherapy , overweight(BMI 26.6±4.2 kg/m2)

4weeks(8 mg candesartan)

8weeks(16 mg candesartan)

<140/90 mm Hg

Pe

rce

nta

ge

of

pa

tie

nts

with

no

rma

lize

d B

p

100

90

80

70

60

50

40

30

20

10

0

61.6%

83%

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

• Risk of Mortality

The Problems to be solved :

*P<.01 versus other three arms. †One or both parents.

IGT=impaired glucose tolerance.

Caballero AE et al. Diabetes. 1999;48:1856-1862.

Impaired Endothelium-dependent Vasodilation in

People at Risk for T2 DM

13 . 7

10 . 5 9 . 8

8 . 4

0

4

8

12

16

Control Relatives IGT Diabetes

Incre

ase

over

base

line o

f

bra

chia

l art

ery

dia

mete

r (%

)

†

*

1st-degree relatives

Change in Malondialdehyde levels(antioxidant ):

Differing effects of ARBs cand (16mg) , Los(100mg), Irbes (300mg),

Koh KK et al. Atherosclerosis. 2004;177:155-60.

126 Patients with hypertension

%

Change

–20

10

20

30

Placebo

–10

0

Irbesartan

300 mg

Losartan

100 mg

Candesartan

16 mg

P = 0.05 by ANOVA

-30

Change in Tissue factor activity level:

Differing effects of ARBs cand (16mg) , Los(100mg), Irbes (300mg),

Koh KK et al. Atherosclerosis. 2004;177:155-60.

126 Patients with hypertension 20

%

Change

–20

10

Placebo

–10

0

Irbesartan

300 mg

Losartan

100 mg

Candesartan

16 mg

P = 0.001 by ANOVA

-30

-40

-50

Change in monocyte chemoatractant protein-1(pg/ml):

Differing effects of ARBs cand (16mg) , Los(100mg), Irbes (300mg),

Koh KK et al. Atherosclerosis. 2004;177:155-60.

126 Patients with hypertension

pg/ml

Candesartan 16 mg Irbesartan 300 mg Placebol

Losartan 100 mg

basal

0

50

100

150

200

250

basal 2 ml 2 m basal 2 m

182 195

212 210

192 198

basal 2 m

202

172

P < 0.05

Change in PAI-1 antigen levels:

Differing effects of ARBs cand (16mg) , Los(100mg), Irbes (300mg),

Koh KK et al. Atherosclerosis. 2004;177:155-60.

%

Change

–40

20

40

60

Placebo

80

–20

0

Irbesartan

300 mg

Losartan

100 mg

Candesartan

16 mg

P < 0.01

P = 0.012 P = 0.163

126 Patients with hypertension

PAI-1 release: Differing effects of ACEinhibition vs

AT1 receptor blockade

Ramipril 10 mg

Losartan 100 mg

–20

–15

–10

–5

0

5

10

15

1 3 4 6

Weeks

in

PAI-1

antigen

(ng/mL)

Brown NJ et al. Hypertension 2002;40:859-65.

P = 0.043, drug x time interaction

20 insulin-resistant, hypertensive patients treated for 6 weeks

Relative Effects of

Telmisartan (40mg/day),

Candesartan

(8 mg/day)

and Losartan

(50 mg/day)

on Alleviating Arterial

Stiffness in Patients with

Hypertension Complicated

by Diabetes Mellitus:

An Evaluation Using the Cardio-

Ankle Vascular Index (CAVI)

The J.Intern. Med. Res.2008;

36: 1094 – 1102

Angiotensin II Type-I Receptor Blocker, Candesartan(8 mg of

candesartan)Improves Brachial-Ankle Pulse Wave Velocity

Independent of Its Blood Pressure Lowering Effects in Type 2

Diabetes Patients Systolic

Diatolic

Inter Med 47: 2013-2018, 2008 CCB; amlodipine (5 mg)or nifedipine(40 mg)

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

• Risk of Mortality

The Problems to be solved :

Nathan DM. N Engl J Med. 2002;347:1342-1349; Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789.

Natural History of Type 2 Diabetes

Type 2 diabetes

Years from

diagnosis

0 5 -10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin secretion

Insulin resistance

Post-meal glucose

Cardiovascular complications Fasting glucose

Microvascular complications

Impaired fasting

glucose

“Metabolic Syndrome”

Hypertension trials

90

60

50

40

30

20

10

0

80

70

Incidence of new onset diabetes in various

21

HO

PE

44

30 27

34

ACEIs

23 25

ARBs Mancia et al 2006 Yusuf et al. Circulation 2005 Abuissa et al J Am Coll Cardiol 2005

87

63

36

90

60

50

40

30

20

10

0

80

70

Incidence of new onset diabetes in various

ARB (candesartan)

Heart failure trials

22

40

64

ACEIs

Mancia et al 2006 Yusuf et al. Circulation 2005 Abuissa et al J Am Coll Cardiol 2005

Coronary artery disease

63%

Candesartan

Vs ACEIs

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

• Risk of Mortality

The Problems to be solved :

Abdominal obesity and increased risk of CHD

Waist circumference was independently associated with increased

age-adjusted risk of CHD, even after adjusting for BMI and other CV

risk factors

0.0

0.5

1.0

1.5

2.0

2.5

3.0

<69.8 69.8-<74.2 74.2-<79.2 79.2-<86.3 86.3-<139.7

1.27

2.06 2.31

2.44 p for trend = 0.007

Re

lati

ve

ris

k

Rexrode et al 1998

Quintiles of waist circumference (cm)

ACEI outcome trials in CAD patients

without HF: Totality of trial evidence

MI

Stroke

All-cause death

Event rate (%)

Favors ACEI ACEI

Revascularization

Favors placebo Placebo

7.5

6.4

2.1

15.5

8.9

7.7

2.7

16.3

0.86

0.86

0.77

0.93

0.0004

0.0004

0.0004

0.025

0.5 0.75 1.25 1 Odds ratio

P

Pepine CJ, Probstfield JL. Vasc Bio Clin Pract.

CME Monograph; UF College of Medicine. 2004;6(3).

HOPE, EUROPA, PEACE, QUIET

With Similar BP reduction , Candesartan decreases

atherosclerosis Vs Amlodipine

Journal of Hypertension 2007, 25:883–889 in Male apoE-deficient mice

Candesartan stops atherosclerotic disease

progression

Journal of Hypertension 2007, 25:883–889

in Male apoE-deficient mice with established atherosclerosis.

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

- New Outcome Data

• Risk of Mortality

The Problems to be solved :

Baseline and final values of blood pressure, intima-media thickness and

coronary flow reserve

Journal of Hypertension: 24(10); 2006,p 2109-2114

Effect of candesartan on coronary flow reserve in

patients with systemic hypertension

Effect of candesartan on coronary flow reserve in patients with

systemic hypertension.

Candesartan improves the CFR in

hypertensive patients. The improvement

was not related to BP control or LVMI

regression. Patients with a lower CFR

show a better response to candesartan.

This fact can be demonstrated non-

invasively with echography after 3

months of therapy.

Journal of Hypertension. 24(10):2109-2114, October 2006

Effects of low-dose angiotensin II receptor blocker candesartan

on cardiovascular events in patients with coronary artery disease

-1ry

end point :a

composite of

revascularization,

nonfatal MI, or

cardiovascular

death

-2nd

end point :

hospitalization for

cardio-vascular

causes.

Relatively low-dose candesartan (4 mg/d), which did not alter

blood pressure levels, reduces cardiovascular risk in high-risk

patients with CAD.

Kondo J et al,2003,146 ( 6) 1022-1027

• Hypertension

• Endothelial Dysfunction

• Risk of New Onset Diabetes

• Risk of Cardiovascular Complications

• Risk of Mortality

- New Outcome Data

The Problems to be solved :

Month 1 2 36m

Amlodipine 2.5, 5, 10mg

Candesartan 4, 8,12 mg (2mg for renal impairment)

R

ISH,2006

0

When the response is insufficient with Ca,titrate CA(no restriction for titration

When the response is insufficient with Am,titrate Am(no restriction for titration)

Amlodipine 2.5,5,10 mg

When the response is insufficient with Am,add D,BB,

When the response is insufficient with Am,add D,BB,

The Candesartan Antihypertensive Survival Evaluation in Japan

(CASE-J) study .Trial of cardiovascular events in high risk

hypertensive patients

* N=4728 high risk hypertensives (SBP ≥ 180 mm Hg or DBP ≥ 110 mm Hg).

*20-85Y (mean age 63.8 years)

*minimum follow-up=3y

N = 4728 high risk hypertensives

Results of CASE-J Study :

Candesartan decrease RRR of Mortality in overweight/Obese

Hypertensive Patients Vs Amlodipine

RRR

ISH,2006

Candesartan Better Amlodipine Better

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Variable Relative risk P value

P=0.969 -Combined Mortality and morbidit

- All cause mortality

All cause - mortality (BMI > 27.5 Kg /m2)

-New onset diabetes

-New onset diabetes (BMI > 27.5 Kg /m2)

- Renal events

P=0.303 15%

P=0.045 49%

P=0.03 36%

P>0.05 10%

P=0.01 63%

Can we solve the problem?

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If a human …………………… Rx ATACAND

WC and Age (mean) in Women

Waist Circumference and Magnitude of Risk among Egyptians: number of risk

Source: Egyptian NHP (1991-1994)

Waist Circumference in NT Egyptians: Frequency Distribution