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