St

1
Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007

2
Managing Cardiometabolic Risk The Role of the
Endocannabinoid System

• Rattan Juneja, MDAssistant Professor of Clinical
  MedicineMedical Director, Indiana University
  Diabetes CenterIndiana University School of
  MedicineIndianapolis, Indiana

3
What percentage of your patients with abdominal
obesity are at risk of cardiovascular disease?

1. lt10
2. 10-25
3. 26-50
4. 51-75
5. gt75

4
Faculty Disclosure

• Dr Juneja grant support Novo Nordisk
  Pharmaceuticals Inc, sanofi-aventis speakers
  bureau Amylin Pharmaceuticals, Inc, Eli Lilly
  and Company, Merck Co., Inc, sanofi-aventis.

5
Learning Objectives

• Describe the central and peripheral effects of
  the endocannabinoid system on food intake
• Explore the steps in the management of the
  overweight/obese patient, including the
  implementation of a weight loss strategy
• Discuss the efficacy and safety of long-term
  drugs for the management of abdominal obesity

6
Changing Paradigms in the Assessment of
Cardiovascular Risk
7
Despite Therapeutic Advances, Cardiovascular
Disease Remains the Leading Cause of Death (USA)
Data for 2002
35
No. of deaths(left axis)
Male
30
Female
25
of all deaths(right axis)
20
Number of Deaths (thousands)
All Deaths (male female)
15
10
5
0
National Center for Health Statistics. Health,
United States. 2004 With Chart Book on Trends in
the Health of Americans. Hyattsville, Md 2004.
8
Abdominal Obesity Is Associated With Increased
Risk of CHD

• Waist circumference is independently associated
  with increased age-adjusted risk of CHD, even
  after adjusting for BMI and other CV risk
  factors.

3.0
2.44
2.31
2.5
P for trend .007
2.08
2.0
Relative Risk
1.27
1.5
1.00
1.0
0.5
0.0
lt69.8 69.8-lt74.2 74.2-lt79.2 79.2-lt86.3 86.3-lt139.
7 lt27 in. 27-lt29 in. 29-lt31 in. 31-lt34
in. 34-lt55 in.
Quintiles of Waist Circumference (cm)
CHD coronary heart disease BMI body mass
index CV cardiovascular.
Rexrode KM, et al. JAMA. 19982801843-1848.
9
Abdominal Obesity Is Associated With Increased
Risk of Developing Diabetes
24
20
16
Relative Risk
12
8
4
0
lt71 lt27.9 in.
71-75.9 27.9-29.8 in.
76-81 29.9-31.9 in.
81.1-86 32-33.9 in.
86.1-91 34-35.8 in.
gt96.3 gt38 in.
91.1-96.3 35.9-37.9 in.
Waist Circumference (cm)
Carey VJ, et al. Am J Epidemiol. 1997145614-619.
10
Measuring Waist Circumference

• To measure waist circumference, locate the upper
  hip bone and the top of the right iliac crest.
  Place a measuring tape in a horizontal plane
  around the abdomen at the level of the iliac
  crest. Before reading the tape measure, ensure
  that the tape is snug, but does not compress the
  skin, and is parallel to the floor. The
  measurement is made at the end of a normal
  expiration.

NHLBI Expert Panel. The Practical Guide The
Identification, Evaluation, and Treatment of
Overweight and Obesity Adults. Bethesda, Md
NHLBI June 1998. NIH Publication 4083.
11
According to the AHA/NHLBI, which of the
following are established cardiometabolic risk
factors?

1. Men and women with HDL 45
2. C-reactive protein levels 0.6 mg/dL
3. LDL-C 200 mg/dL
4. None of the above

12
AHA/NHLBI Cardiometabolic Risk Factors
(formerly Metabolic Syndrome)
Risk Factor Defining Level
Waist circumference
MenWomen gt102 cm (gt40 in) gt88 cm (gt35 in)
Triglycerides (TG) ?150 mg/dL
HDL-C
MenWomen lt40 mg/dLlt50 mg/dL
Blood pressure ?130 or ?85 mm Hg
Fasting glucose ?100 mg/dL
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 (gt90 cm
in men and gt80 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.
13
Interrelationships Between Insulin Resistance
and Atherosclerosis
Insulin Resistance
Obesity
HBP
Inflammation
? Insulin
Diabetes
? TG
Small dense LDL-C
Low HDL-C
? Coag
Endothelial Dysfunction Atherosclerosis
HBP high blood pressure LDL-C low-density
lipoprotein cholesterol Coag coagulation.
Used with permission of Henry N. Ginsberg, MD
14
What is the value of evaluating patients
forcardiometabolic risk factors?

1. It is a prognosticator of short-term risk
2. It is a prognosticator of long-term risk
3. It is a prognosticator of both short- and
   long-term risk
4. It has no prognostic value

15
Substantial Residual Cardiometabolic Risk in
Statin-treated Patients
The MRC/BHF Heart Protection Study
30
Placebo Statin
20
Risk reduction 24 (P lt.0001)
Patients
19.8 of statin-treatedpatients had a majorCV
event within 5 years
10
0
0
1
2
3
4
5
6
Year of Follow-up
Adapted from Heart Protection Study Collaborative
Group. Lancet. 20023607-22.
16
Medical Need for Cardiometabolic Risk Reduction
Unmet Medical Need
Classical Risk Factors
Cluster of Novel Risk Factors
?HDL-C
Adiponectin
Insulin Resist
? Smoking
? LDL-C
? BP
AbdominalObesity
T2DM
?Glu
?TG
?CRP
Anti- Hyper- tensives
Statins
Anti- Smoking Programs
CARDIOVASCULAR DISEASE
BP blood pressure CRP c-reactive proteins
Glu glucocorticoids T2DM type 2 diabetes
mellitus. Modified from Grundy S. J Am Coll
Cardiol. 2006471093-1100 Grundy S. Nat Rev
Drug Discov. 20065295-309.
17
Management of Cardiometabolic Risk Factors

• First-line therapy directed toward major risk
  factors
• ? LDL-C to target levels
• ? BP to target levels
• ? Plasma glucose
• Target modifiable underlying risk factors
• Obesity
• Physical inactivity
• Atherogenic diet
• Smoking

18
Treatment Options forAbdominal Obesity
19
A Guide to Selecting TreatmentNIH Guidelines
BMI Category
Treatment
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 Yes surgery
comorbidities
40
25-26.9
27-29.9
30-34.9
35-39.9
NIH National Institutes of Health. NHLBI Expert
Panel. The Practical Guide The Identification,
Evaluation, and Treatment of Overweight
andObesity Adults. Bethesda, Md NHLBI June
1998. NIH Publication 4083.
20
Diet, Exercise, and Behavioral Modification

• Diet
• Caloric intake should be reduced by 500-1000
  kcal/day from current levels
• 1000-1200 kcal/d for women
• 1200-1600 kcal/d for men (or women 165 lb)
• Exercise
• Walking, dancing, individual or team sport
• Goal of 30 min moderate intensity exercise daily
• Behavioral modification
• Self-monitoring
• Stress management
• Cognitive restructuring
• Social support

Wadden T, et al. N.H.L.a.B. Institute, Editor.
2000, NIH.
21
Orlistat Mechanism of Action
FA fatty acid MG monoglyceride TG
triglyceride.
Slide source www.obesityonline.org
Yanovski SZ, et al. N Engl J Med.
2002346591-602.
22
Orlistat

• Available OTC (June 2007)
• Orlistat 60 mg t.i.d. (6 months) in
• Low overweight (consumer defined)
• BMI 25 lt28 kg/m²
• High overweight (consumer defined)
• BMI 28 29.9 kg/m²
• Daily dose limited to 6 pills/day 18 years
• In combination with hypocaloric diet and
  moderate exercise
• 6-month weight loss

OTC over the counter. Joint Nonprescription
Drugs and Endocrinologic and Metabolic Drugs
Advisory Committee January 23, 2006
23
Orlistat Efficacy at 60 and 120 mg Weight Change
From Baseline (LOCF)
BM14149 Mth 6
BM14149 Mth 6
NM14161 Mth 6
NM14161 Mth 6
NM17247 Mth 4
NM17247 Mth 4
10
5
0
Weight Change From Baseline (kg)
-5
-10
-15
-20
PLA
60
120
Pooled studies of orlistat 60 mg t.i.d. and 120
mg t.i.d. versus placebo LOCF last observation
carried forward.
Joint Nonprescription Drugs and Endocrinologic
and Metabolic Drugs Advisory Committee January
23, 2006
24
Orlistat Efficacy in Reducing Body Weight and
Glycemic Markers
Orlistat 120mg (n 162) Placebo (n 159) Statistical Significance
of patients who discontinued oral sulfonylurea 11.7 7.5 P .05
of patients who decreased dose of oral sulfonylurea 31.5 21.4 P .05
Body weight change (lb) -8.9 -4.2 P .05
HbA1c -0.18 0.28 P .05
Fasting glucose mmol/L -0.02 0.54 P .05
Fasting insulin pmol/L 19.68 -18.02 Not significant
Modified from Physicians Desk Reference. 59th ed.
Montvale, NJ Thomson PDR 20052951-2955.
25
Orlistat GI Side Effects
Pooled analysis of obese patients from seven
orlistat double-blind placebo controlled trials.
(Orlistat n 1933, Placebo n 1466) GI
gastrointestinal.Henness, S. and C.M. Perry.
Drugs, 2006661625-1656.
26
Sibutramine Blocks Neuronal Monoamine (Serotonin,
Norepinephrine, Dopamine) Reuptake
monoamine S sibutramine.
Slide source www.obesityonline.org
Yanovski SZ, et al. N Engl J Med.
2002346591-602.
27
STORM Study Sibutramines Effects on
Cardiometabolic Risk Factors
Intention-to-Treat Population at 24 Months
0
25
? from baseline P lt.001.
20.7
20
15
11.2
10
5
Change
0
-5
-3.75
-10
-15
-20
-18.5
-25
HDL-C
TG
All sibutramine treated (n 206)
All sibutramine treated (n 222)
All placebo treated (n 57)
All placebo treated (n 62)
Adapted from James WP, et al. Lancet.
20003562119-2125.
28
Adverse Effects of Sibutramine Therapy
Subjects ()Adverse Effect Placebo
Sibutramine
Dry mouth 4.2 17.2 Constipation 6.0 11.5 Insom
nia 4.5 10.7 Dizziness 3.4 7.0 Hypertension 0
.9 2.1 Tachycardia 0.6 2.6 Palpitation 0.8 2.
0
Meridia (sibutramine hydrochloride monohydrate)
Prescribing Information, Abbott Laboratories,
North Chicago, Ill.
29
Lifestyle Management vs Pharmacotherapy for
Obesity
0
2
4
Sibutramine alone
6
Lifestyle modification
Weight Loss (kg)
8
Sibutramine brief therapy
10
12
Combined therapy
14
16
0
3
6
10
18
40
52
Weeks
In a study of N 224 obese patients randomized
to receive sibutramine 15 mg or lifestyle
modification with the Lifestyle, Exercise,
Attitudes, Relationships and Nutrition (LEARN)
Program or both. Combined therapy resulted in the
greatest weight loss.
Wadden TA, et al. N Engl J Med.
20053532111-2120.
30
Bariatric Surgery

• Indicated for BMI 40 kg/m2 or BMI 35 kg/m2 and
  a comorbidity
• The only treatment modality that results in
  substantial 10-year weight loss
• Results in long-term reduction in energy intake
  and is associated with increased physical
  activity
• Surgery has not been demonstrated to reduce
  long-term mortality long-tem randomized trials
  not yet available
• Mortality is approximately 0.1 for gastric
  banding, 0.5 for gastric bypass, and 1.1 for
  biliopancreatic diversion or duodenal switch
  procedures

Thompson WG, et al. Mayo Clin Proc.
20078293-101.
31
The Endocannabinoid System (ECS)
32

Endocannabinoid SystemStress Recovery System

• 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 as needed
• Act locally and are rapidly metabolized

DiMarzo V, Matias I. Nat Neurosci.
20058585-589. Grotenhermen F. Neuro Endocrinol
Lett. 20042514-23.

33
History of the ECS

1964 Isolation of ?9-THC, the active
constituent of Cannabis sativa
1988 High-affinity cannabinoid binding sites
were discovered in rat brain

?9-Tetrahydrocannabinol


1995 Isolation of a second EC ligand, 2-AG
(from gut and brain)
Modified from ESC Finer Wellcome Trust CRF
Addenbrooke Hosp. Gaoni Y, et al. J Am Chem Soc.
1964861646-1647 Devane WA, et al. Mol
Pharmacol. 198834605-613 Matsuda LA, et al.
Nature. 1990346561-564 Gerard CM, et al.
Biochem J. 1991279129-134 Devane WA, et al.
Science. 19922581946-1949 Munro S, et al.
Nature. 199336561-65 Sugiura T, et al. Biochem
Biophys Res Commun. 199521589-97.


34
The ECS Receptors and Ligands

• Receptors
• 7-member transmembrane G-protein coupled receptor

CB-1
CB-2
Immune System
Adipose Tissue
GI Tract
Liver
Pancreas
Brain
Muscle
Endogenous Ligands (Endocannabinoids)
O
O
O
H
O
H
O
H
N
C
H
O
H
Anandamide (AEA)
2-Arachidonoyl Glycerol

• Synthesized from membrane-derived phospholipids
• Taken up and degraded rapidly
• Act as retrograde messengers

Engeli S, et al. Diabetes. 2005542838-2843
Jbilo O, et al. FASEB J. 2005191567-1569
Osei-Hyiaman D, et al. J Clin Invest.
20051151298-1305 Di Marzo V, et al. Nat
Neurosci. 20058585-589.
35
Endocannabinoids Act as Retrograde Messengers in
the Brain

• Excitation of neuron causes depolarization,
  influx of calcium ions stimulates synthesis of
  ECs in postsynaptic neurons
• ECs freely diffuse, bind to CB1 receptors on
  presynaptic terminals of neurons that form
  synapses with stimulated neuron reduces the
  release of inhibitory neurotransmitters.
  Inhibition of neurotransmitter release is blocked
  by antagonists of CB1 receptor.
• ECs are taken up by transporter, broken down by
  the membrane-bound fatty acid amide hydrolase. EC
  availability to activate presynaptic CB1
  receptors is regulated by uptake and degradation.

Kreitzer AC, et al. Curr Opin Neurobiol.
200212324-330.
36
CB1 ReceptorMediated Activity
Stimulated by agonist (eg, marijuana)
Increased receptor- mediated activity
Resting state (basal activity)
Decreased receptor- mediated activity
Effect of selective antagonist
37
Sites of CB-1 Receptors and Effects of CB-1
Blockade
Site of Action Mechanism(s) Clinical Implications
Hypothalamus/Nucleus accumbens ? Food intake Body weight Abdominal obesity
Adipose tissue ? Adiponectin ? Lipid accumulation Dyslipidemia Insulin resistance
Muscle ? Glucose uptake Insulin resistance
Liver ? Lipogenesis ? Fatty acid synthesis Dyslipidemia Insulin resistance
Di Marzo V, et al. Nature. 2001410822-825
Ravinet Trillou C, et al. Am J Physiol Regul
Integr Comp Physiol. 2003284R345-R353 Cota D,
et al. J Clin Invest. 2003112423-431 Pagotto
U, et al. Endocr Rev. 20062773-100 Van Gaal
LF, et al. Lancet. 20053651389-1397 Liu YL, et
al. Int J Obes. 200529183-187 Osei-Hyiaman D,
et al. J Clin Invest. 20051151298-1305.
38
CB-1 Antagonists in Development
Pharmaceutical Company Drug Name Development Phase NDA Filing Status
sanofi-aventis SR-141716 (Rimonabant) III NDA filed and withdrawn 2007
Merck MK-0364 III 2008
Pfizer CP 945,598 CP 741,952 III II ? ?
BMS-Solvay BMS-646256 II ?
Financial News. Merck Remains Confident in
Future Growth as it Executes on New Strategy.
Available at http//www.merck.com/newsroom/press_
releases/financial/2006_1212.html. Accessed
October 9, 2007 ClinicalTrials.gov. NIH.
Available at www.clinicaltrials.gov. Accessed
October 9, 2007.
39
RIO (Rimonabant in Overweight/Obesity) Trials
(gt6600 patients enrolled)
Study Population N Design
RIO North America Obese or overweight with/without comorbidities (excluding diabetes) 3045 11 year Rerandomized
RIO Europe Obese or overweight with/without comorbidities (excluding diabetes) 1507 2 years
RIO Lipids Obese or overweight with untreated dyslipidemia (excluding diabetes) 1036 1 year
RIO Diabetes Obese or overweight with type 2 diabetes 1045 1 year
Pi-Sunyer FX, et al. JAMA. 2006295761-775 Van
Gaal LF, et al. Lancet. 20053651389-1397
Després JP,et al. N Engl J Med.
20053532121-2134 Scheen AJ, et al. Lancet.
20063681660-1672.
40
RIO Trials Study Design
Placebo run-in single-blind
Screening
Treatment period 1 or 2 years, double-blind
Rerandomization RIO NA
Mild hypocaloric diet, reduced by 600 kcal/day
Placebo
Placebo
Placebo
Rimonabant 5 mg
Rimonabant 5 mg
Placebo
Rimonabant 20 mg
Rimonabant 20 mg
Week 52 Inclusion Randomization
Week 0 Inclusion Randomization
Week -4
Week -6
Week 104
Pi-Sunyer FX, et al. JAMA. 2006295761-775 Van
Gaal LF, et al. Lancet. 20053651389-1397
Després JP, et al. N Engl J Med.
20053532121-2134 Scheen AJ, et al. Lancet.
20063681660-1672.
41
Consistent Weight Change Over 1 Year RIO NA, RIO
Lipids, RIO Europe (ITT, LOCF)
0
RIO North America
-2
-4
Weight Change (kg)
RIO Lipids
-6
-8
RIO Europe
P lt.001 vs placebo.
-10
0
16
32
40 52 LOCF
ITT intention to treat
Week
Pi-Sunyer FX, et al. JAMA. 2006295761-775 Van
Gaal LF, et al. Lancet. 20053651389-1397
Després JP, et al. N Engl J Med.
20053532121-2134.
42
Which of the following confers the greatest risk
for cardiovascular disease in a patient with
visceral obesity?

1. Hypertension
2. Atherogenic diet
3. Type 2 diabetes
4. Low serum HDL

43
RIO Lipids Changes in C-Reactive Protein and
Adiponectin at 1 Year ITT LOCF
CRP (mg/L)
Adiponectin (?g/mL)
Baseline 5.3 5.0
Baseline 5.7 5.9
N 313 N 320
0
-0.4
-1
-0.9
Change From Baseline
-2
Change From Baseline
P .02
-3
Rimonabant 20 mg
Placebo
Medians.
Després JP, et al. N Engl J Med.
20053532121-2134.
44
Placebo-Subtracted Weight and Waist
ReductionsRIO Program (ITT, LOCF)
Rimonabant 20 mg Minus Placebo
RIO North America
RIO Europe
RIO Lipids
RIO Diabetes
0
-2
Weight Loss (kg)
-3.9
-4.7
-4.7
-4

-5.4


P lt.001

-6
0
-2
-3.3
-3.6
Waist Loss (cm)
-4.2
-4.7
-4




-6
Pi-Sunyer FX, et al. JAMA. 2006295761-775 Van
Gaal LF, et al. Lancet. 20053651389-1397
Després JP, et al. N Engl J Med.
20053532121-2134 Scheen AJ, et al. Lancet.
20063681660-1672.
45
RIO DiabetesChange in HbA1c Over 1 Year (ITT,
LOCF)
0.1 0.1
0.2
0.0
-0.1 0.1
-0.2
-0.7
Change in HbA1c ()
-0.4
-
-0.6
-0.6 0.1
-0.8
0
24
12
36
52
Week
ITT analysis Rimonabant 5 mg vs placebo P
.034 Rimonabant 20 mg vs placebo P lt.001
Scheen AJ, et al. Lancet. 20063681660-1672.
46
SERENADE Rimonabant in Diabetics With Multiple
Cardiometabolic Risk Factors Changes From
Baseline (ITT, LOCF)
SERENADE Study Evaluating Rimonabant Efficacy
in Drug-NAive DiabEtic Patients. SERENADE
Confirms Efficacy of Rimonabant in Diabetes.
Available at http//www.medscape.com/viewarticle/
548932. Accessed Febraury 3, 2006 Iranmanesh A,
et al. Diabet Med, 200623200-410.
47
Efficacy Summary

• 4 studies in gt6600 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
• Rimonabant 5 mg did not show consistent results
  for all studied parameters

48
Which of the following statements about
rimonabant is true?

1. Rimonabant decreases the release of adiponectin
2. Rimonabant has a dual mechanism of action,
   working both centrally and peripherally
3. Rimonabant results in significant decreases in
   LDL-C
4. None of the above

49
Obesity Program - Overall Safety
Rimonabant 20 mg (n 2415)
Rimonabant 5 mg (n 2220)
Placebo (n 1848)
85.2
82.4
81.4
Patients with any AE
7.0
6.4
4.5
Patients with any serious AE
17.5
12.2
8.5
Patients permanently discontinued due to AE
Obesity program (RIO-Europe, RIO-North
America, RIO-Lipids, RIO-Diabetes, REBA, EFC5745,
and ACT3801) Original assessment from the
investigator AE treatment-emergent adverse
event.

Data on file, sanofi-aventis.
50
Obesity Program Adverse Events gt2
Data on file, sanofi-aventis.
51
Obesity Program Discontinuations gt0.5 Per
Investigator
Data on file, sanofi-aventis.
52
Obesity Program Depression-related Events
Overall Incidences
Obesity program (RIO-Europe, RIO-North America,
RIO-Lipids, RIO-Diabetes, REBA, EFC5745, and
ACT3801) N taking into account any patient
exposure
Data on file, sanofi-aventis.
53
Rimonabant 20 mg vs Placebo Incidence of
Suicidality
Odds Ratio for Incidence of Suicidality 20 mg
Rimonabant vs Placebo
Population OBE (DIA)OBE (Ph2)OBE (CRA) OBE (EUR) OBE (DIA) OBE (LIP) OBE (N.A.) SMOKING SMOKING SMOKING SMOKING ALCOHOL SCHIZOPH OBE (BED) Study EFC4736DRI3388EFC5031EFC4733EFC5825EFC4735EFC4743EFC4796EFC4474EFC5794EFC4964ACT4855METATRIACT3801 20 mg n/N() 2/339 (0.59)1/69 (1.45)1/76 (1.32)6/599 (1)1/138 (0.72)3/346 (0.87)7/1219 (0.57)12/3023 (0.40)2/267 (0.75)2/262 (0.38)0/26 (0)3/131 (2.29)7/72 (9.72)0/143 (0) Plb n/N () 0/348 (0)0/73 (0)0/80 (0)1/305 (0.33)0/140 (0)2/342 (0.58)4/607 (0.66)0/2016 (0)1/260 (0.38)1/268 (0.37)1/261 (0.38)3/127 (2.36)7/98 (7.14)0/146 (0) OR 5.23.23.23.13.11.50.916.72.01.00.31.01.4NA
1.9 1.1, 3.1
Overall Suicidality Summary
0.1
0.5
1.0
3.0
10.0
20.0
50.0
Rimonabant Better
Rimonabant Worse
Odds ratios for suicidality of rimonabant 20 mg
vs placebo across rimonabant clinical trials.
Results were most consistent in the obesity
trials but varied significantly in the smoking
trials
Egan AG, et al. FDA Briefing Document NDA 21-888.
Zimulti (rimonabant) Tablets, 20mg Sanofi Aventis
Advisory Committee. June 13, 2007. In Meeting
EaMDAC, ed FDA 2007.
54
Rimonabant Clinical Safety Summary

• Safety assessment based on extensive exposure up
  to 2 years
• The most frequent adverse events which led to
  drug discontinuation were depression, mood
  alteration, nausea, and anxiety
• Psychiatric events
• Increased incidence of depression-related events
  and anxiety with rimonabant vs placebo, overall
  incidence remained relatively low
• Suicide and suicidal ideation were the most
  serious psychiatric adverse events
• Efforts are underway to determine methods of
  identifying patients at risk before and during
  treatment (eg, patients with a history of major
  depression)
• Similar qualitative characteristics between
  rimonabant 20 mgand placebo
• No clinical changes in laboratory test,
  electrocardiogram, or vital signs
• Long-term exposure did not identify new or
  increased risks and supports its long-term
  administration in overweight/obese patients with
  at least one cardiometabolic risk factor

Data on file, sanofi-aventis.
55
Which patients are NOT candidates for
CB-1antagonist therapy?

1. Patients with a history of major depression
2. Patients with a history of alcoholism
3. Patients who abuse marijuana
4. All of the above

56
Case Study
57
Case Chief Complaint

• The patient is an abdominally obese male who has
  a sedentary job as a computer science professor
• He has recently relocated from another city
• The patient is somewhat anxious and concerned
  about his diagnosis of hypertension, high
  cholesterol/high triglycerides, and more
  recently T2DM
• The patient is well educated and concerned about
  his increased risk for cardiovascular disease

58
Case History

• Hypercholesterolemia, hypertriglyceridemia, and
  hypertension diagnosed 10 years ago
• Prediabetes with elevated fasting glucose 2
  years ago
• Smoker 1 pack per day for 27 years. He has tried
  to quit several times in the past
• Diet
• Reduced calorie diet (1800 kcal/day)
• Medications
• Irbesartan 300 mg qd (angiotensin II receptor
  blocker)
• Amlodipine 10 mg qd

59
Office Physical

• Current weight 280 lb (120 kg)
• Height 6'3?
• Body mass index 35
• Waist circumference 46 inches
• Head/Ears/Eyes/Neck/Throat Within normal limits
• Chest Clear to AP
• Abdomen No palpable masses
• Extremities 2 pitting edema, otherwise within
  normal limits

60
Measuring Waist Circumference

• To measure waist circumference, locate the upper
  hip bone and the top of the right iliac crest.
  Place a measuring tape in a horizontal plane
  around the abdomen at the level of the iliac
  crest. Before reading the tape measure, ensure
  that the tape is snug, but does not compress the
  skin, and is parallel to the floor. The
  measurement is made at the end of a normal
  expiration.

NHLBI Expert Panel. The Practical Guide The
Identification, Evaluation, and Treatment of
Overweight and Obesity Adults. Bethesda, Md
NHLBI June 1998. NIH Publication 4083.
61
Laboratory Tests

• TG 250 mg/dL
• TC 280 mg/dL
• LDL-C 200 mg/dL
• HDL-C 30 mg/dL
• Fasting glucose 104 mg/dL
• 2-hour postprandial glucose 210 mg/dL

62
Assessment

• Abdominal obesity
• T2DM
• Hypertension
• Hypertriglyceridemia
• Hypercholesterolemia
• Tobacco abuse

63
What is the best way to manage overweight and
obese patients according to NIH guidelines?

1. Diet, exercise, and behavioral modification alone
2. Bariatric surgery
3. Management depends on the patients BMI
4. Pharmacologic agents

64
What would be the next best step in management?

1. Refer the patient to a behavioral modification
   program while continuing a 600-kcal hypocaloric
   diet, moderate exercise, and refer the patient
   for bariatric surgery
2. Refer the patient to a behavioral modification
   program while continuing a 1400-kcal hypocaloric
   diet, moderate exercise, and begin orlistat 120
   mg po q8h
3. Refer the patient to a behavioral modification
   program while continuing a 1400-kcal hypocaloric
   diet, moderate exercise, and begin phentermine
   37.5 mg po qd for 6 months
4. None of the above

65
Plan

• The physician writes a prescription for
  metformin.
• Additionally the physician recommends a nicotine
  patch to assist with smoking cessation
• The physician discusses the currently available
  medications approved for long-term management of
  abdominal obesity, orlistat and sibutramine
• The physician discusses the side effect profile
  with the patient and recommends a trial of
  orlistat (120 mg q8h) with instructions to follow
  up in 3 months

66
Second Office Visit

• The patient returns after 8 weeks complaining of
  abdominal bloating, gas, and diarrhea
• Patient recounts story of attending a dinner
  party at the university presidents house and had
  some very embarrassing moments while at the party
• The physician re-measures the waist circumference
  and weight
• The patient has lost 8 lbs and his waist
  circumference is now 45 inches
• The physician and the patient decide to
  discontinue orlistat and try sibutramine

67
Third Office Visit

• The patient returns for a follow-up visit after
  3 weeks
• The doctor notices patient has hypertension. He
  is concerned this may be related to sibutramine,
  so he decides to discontinue the drug
• The physician explains that therapeutic options
  for abdominal obesity are currently limited, but
  there are new therapies in development that may
  help fill this need

68
Thank You
69
Q A
70
PCE Takeaways

• Identify patients at increased cardiometabolic
  risk by measuring waist circumference and
  assessing the patient for hypertriglyceridemia,
  elevated fasting glucose, hypertension, or low
  HDL
• Identify patients motivated to lose weight.
  Evaluation of readiness should
  include
• Encouraging support from family and friends
• Ensuring that the patient/family understands the
  risks and benefits
• Encouraging the patient to make the time and
  commitment
• Implement a weight-loss program that includes a
  hypocaloric diet, exercise and behavioral
  modification
• CB-1 antagonists can lead to weight loss
  resulting in improvements in
• Atherogenic dyslipidemia (HDL and TG)
• Glycemic variables and fasting insulin
• Body weight and waist circumference
• ?CRP and ?adiponectin

71
What percentage of your patients with abdominal
obesity would you consider treating to reduce
their cardiometabolic risk?

1. lt10
2. 10-25
3. 26-50
4. 51-75
5. gt75

72
Lunch Dont forget to complete and returnyour
CME/CE evaluation form and follow-up
questionnaire to the registration desk at the end
of our program
73
Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007