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Abdominal Obesity and Cardiometabolic Risk: The Role of the Endocannabinoid System

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Gout. Cholecystitis. Colon (?Breast) Cancers ... Gout. Gall Bladder. Disease. Some Cancers. What Is Cardiometabolic Risk? Diabetes: A Genetic Legacy ... – PowerPoint PPT presentation

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Title: Abdominal Obesity and Cardiometabolic Risk: The Role of the Endocannabinoid System


1
Abdominal Obesity and Cardiometabolic Risk The
Role of the Endocannabinoid System
2
(No Transcript)
3
Obesity Trends Among U.S. Adults 1985-2001
4
Obesity Trends Among U.S. Adults 1985-2001
5
Obesity Trends Among U.S. Adults 1985-2001
6
Obesity Trends Among U.S. Adults 1985-2001
7
Obesity Trends Among U.S. Adults 1985-2001
8
Obesity Trends Among U.S. Adults 1985-2001
9
Obesity Trends Among U.S. Adults 1985-2001
10
Obesity Trends Among U.S. Adults 1985-2001
11
Obesity Trends Among U.S. Adults 1985-2001
12
Obesity Trends Among U.S. Adults 1985-2001
13
Obesity Trends Among U.S. Adults 1985-2001
14
Obesity Trends Among U.S. Adults 1985-2001
15
Obesity Trends Among U.S. Adults 1985-2001
16
Stroke
Heart Disease
Hypertension
Hyperlipidemia
Colon (?Breast) Cancers
Diabetes
OBESITY
Osteoarthritis
Cholecystitis
Depression
Gout
Sleep Disorders
17
Prevalence of Diagnosed Diabetes in the United
States
18
Number of People With Diabetes (millions) for
2000 and 2010 and the Increase
26.5 32.9 24
14.2 17.5 23
84.5 132.3 57
The number of adults with diabetes in the world
is estimated to increase by 122, from 135
million in 1995 to 300 million in 2025
9.4 14.1 50
15.6 22.5 44
1.0 1.3 33
World 2000 151 million 2010 221 million ?
Increase 46
Zimmet P, et al. Nature 2001414(6865)782-787
King H, et al. Diabetes Care 199821(9)1414-1431
19
(No Transcript)
20
Stroke
Heart Disease
Hypertension
Hyperlipidemia
Some Cancers
Non-insulin dependent Diabetes Mellitus
OBESITY
Gall Bladder Disease
Osteoarthritis
Mood Disorders
Gout
Heating Disorders
Sleep Disorders
21
What Is Cardiometabolic Risk?
22
Diabetes A Genetic Legacy
23
Estimated Costs of Diabetes in the United
States2002
24
AHA/NHLBI Cardiometabolic Risk Factors(former
Metabolic Syndrome)
Diagnosis is established when ?3 of these risk
factors are present.Some US adults of non-Asian
origin with marginal increases should benefit
from lifestyle changes. Lower cutpoints (90 cm
in men and 80 cm in women) for Asian Americans.
Or on drug treatment for the risk factor.
AHA American Heart Association NHLBI
National Heart, Lung, and Blood Institute HDL-C
high-density lipoprotein cholesterol.
Grundy S, et al. Circulation. 20051122735-2752.
25
Caloric expenditure for various activities
26
A behavior chain showing how behavior, linked to
another, can contribute to an overeating episode.
Buy Cookies
Leave cookies on counter
Home on Saturday afternoon
Tired and bored
Urge to eat
Go to kitchen
Take cookies to den
Eat cookies while watching TV
Eat rapidly until full
Feel guilty like a failure
Restraint weakens further
More eating
27
Medical Need for Cardiometabolic Risk Reduction
CARDIOVASCULAR DISEASE
Modified from S. Grundy. Journal of the American
College of Cardiology.2006471093-100 Grundy S.
Nature Reviews Drug Discovery.20065295-309
28
Waist Circumference is Correlated with Abdominal
Adipose Tissue
Note the high correlation coefficient (r 0.80)
Despres JP, et al. BMJ. 2001322716-720.
29
Interrelationships Between Insulin Resistance
and Atherosclerosis
Insulin Resistance
Obesity
Small dense LDL-C
Low HDL-C
Inflam- mation
HBP
? Insulin
? TG
? Coag
Diabetes
Endothelial Dysfunction Atherosclerosis
HBP high blood pressure TG triglycerides
Coag coagulation.
Used with permission of Ginsberg HN.
30
Modest Weight Loss Dramatically Improves
Cardiometabolic Risk
Modified from Després JP, et al. BMJ.
2001322716-720.
31
Question 3
?
  • Which of the following is associated with a
    higher risk of cardiovascular risk?
  • Waist circumference 40 cm and European ancestry
  • Waist circumference 40 cm and South Asian
    ancestry
  • Fasting glucose of 102 mg/dL
  • A and B only
  • All of the above
  • None of the above

32
A Guide to Selecting TreatmentNIH Guidelines
BMI Category
Treatment 2526.9 2729.9 3034.9 3539.9 ?40 Die
t, physical Yes with Yes with Yes Yes Yes activity
, comorbidities comorbidities behavior therap
y Pharmaco- Yes with Yes Yes Yes therapy
comorbidities Weight-loss Yes with
surgery comorbidities Yes
NIH National Institutes of Health.
The Practical Guide Identification, Evaluation,
and Treatment of Overweight and Obesity in
Adults. NIH/NHLBI/NAASO October 2000. NIH
publication 00-4084.
33
Antiobesity Drugs
  • Currently available weight management agents for
    long term use include orlistat and sibutramine
  • Both agents are effective when taken regularly in
    conjunction with a mildly hypocaloric diet
  • Results are better if
  • Increased activity level is maintained
  • Active lifestyle counseling by physician and
    dietitian accompany therapy
  • Both agents have adverse effects that limit their
    use
  • Orlistat has multiple GI adverse effects (oily
    discharge per rectum) that may lead to social
    embarrassment
  • Sibutramine may lead to unacceptable increases in
    blood pressure

Yanovski SZ, Yanovski JA. N Engl J Med.
2002346591-602. Physicians Desk Reference. 59th
ed. Montvale, NJ Thomson PDR 20052951-2955.
34
Orlistat Mechanism of Action
Mucosal Cell
Intestinal Lumen
LIPASE
LIPASE
TG
Orlistat
FA
MG
LIPASE
Bile Acids
Micelle
FA fatty acid MG monoglyceride TG
triglyceride.
Slide source www.obesityonline.org
Yanovski SZ, et al. N Engl J Med.
2002346591-602.
35
Sibutramine Blocks Neuronal Monoamine
(Serotonin, Norepinephrine, Dopamine) Reuptake
X
S
monoamine S sibutramine.
Slide source www.obesityonline.org
Yanovski SZ, et al. N Engl J Med.
2002346591-602.
36
The Endocannabinoid System
37
Endocannabinoid SystemCentral and Peripheral
Control of Energy Balance
  • The endocannabinoid system (ECS) is a
    neuromodulatory signaling system that plays a
    role in many important physiologic processes
  • Endocannabinoids are endogenously produced
    ligands that bind to and activate cannabinoid
    receptors
  • Derived from phospholipids in the cell membrane
  • Produced on demand
  • Act locally and are rapidly metabolized

DiMarzo V, Matias I. Nat Neurosci.
20058585-589. Grotenhermen F. Neuro Endocrinol
Lett. 20042514-23.
38
The Endocannabinoid System (ECS) Is a Modulatory
System
  • Endocannabinoids
  • Synthesized in response to neuronal activity from
    lipid precursors in postsynaptic cells
  • Activate CB1 receptors presynaptically as
    retrograde messengers
  • Inhibit neurotransmitter release
  • Are degraded immediately
  • CB1 receptors
  • Located on neurons and other cells that play a
    key role in food intake, energy balance, and
    lipid and glucose metabolism

Di Marzo V, Matias I. Nat Neurosci.
20058585589. Di Marzo V, et al. Trends
Neurosci. 199821521528. Wilson RI, Nicholl
RA. Science. 2002296678682.
39
RIO RIMONABANT IN OBESITY
40
RIO (Rimonabant In Overweight/Obesity) Trials
(6600 patients enrolled)
41
RIO North America Change in Weight Over 2 Years
in Rerandomized Patients (ITT, LOCF)
0
Rimonabant 20 mg/Placebo
-2.3
-2
-3.2
-4
Weight Change (kg)
-6
-7.4
-8
-10
0 12 24 36 48
60 72 84 96 104
LOCF
Week
PPi-Sunyer FX, et al. JAMA. 2006295761-775.
42
RIO DiabetesChange in HbA1c Over 1 Year (ITT,
LOCF)
Placebo
0.1 0.1
Rimonabant 5 mg
0.2
Rimonabant 20 mg
0.0
-0.1 0.1
-0.2
Change in HbA1c ()
-0.7
-0.4
-
-0.6
-0.6 0.1
-0.8
0
LOCF
24
12
36
52
ITT analysis R 5 mg vs placebo P.034 R 20 mg
vs placebo PWeek
Scheen A, et al. Presented at the American
Diabetes Association 2005 Annual Meeting.
Available at http//www.incirculation.net/18471_
51200.aspx?usechannel. Last accessed 1/4/06.
43
Efficacy Summary
  • Four studies in 6600 overweight and obese
    subjects with multiple cardiometabolic risk
    factors including diabetes and dyslipidemia
  • Rimonabant 20 mg therapy produced greater
    improvements than placebo in cardiovascular and
    metabolic risk factors
  • Body weight and waist circumference
  • HDL cholesterol and triglycerides
  • Fasting insulin, glucose tolerance, and glycemic
    control
  • CRP and adiponectin
  • Efficacy sustained for 2 years

44
Depression-related Adverse Events in the RIO
Trials
  • Depressive disorders were reported in 3.2 of
    obese patients, or overweight patients with
    associated risk factor(s) treated with rimonabant
    20 mg compared with 1.6 of patients treated
    with placebo
  • These were usually mild or moderate in severity
    and resulted in recovery in all cases either
    after corrective treatment or discontinuation of
    rimonabant
  • These cases did not exhibit any differentiating
    characteristics compared to cases reported in the
    control groups

Pooled 1-year data RIO North America, Rio
Europe, RIO Lipids, and RIO Diabetes.
Available at http//www.emea.eu.int/humandocs/Hum
ans/EPAR/acomplia/acomplia.htm. Summary of
Product Characteristics Section 4.8
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