CVD Critical Pathways Group 2006 Teleconferences

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CVD Critical Pathways Group2006 Teleconferences
October 11, 2006
This activity is supported by an educational
grant from the Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership.
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Faculty

• Gregg C. Fonarow, MD
• Eliot Corday Professor of Medicine
• and Cardiovascular Science
• Director, Ahmanson-UCLA Cardiomyopathy Center
• UCLA Division of Cardiology
• UCLA Medical Center
• Los Angeles, California

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Disclosure Statement

• The Network for Continuing Medical Education
  requires that CME faculty disclose, during the
  planning of an activity, the existence of any
  personal financial or other relationships they or
  their spouses/partners have with the commercial
  supporter of the activity or with the
  manufacturer of any commercial product or service
  discussed in the activity.

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Faculty Disclosure Statement

• Gregg C. Fonarow, MD, has served as a consultant
  to and has received research support and
  honoraria from Bristol-Myers Squibb Company,
  GlaxoSmithKline, Merck Co., Inc., Pfizer Inc,
  sanofi-aventis, Schering-Plough Corporation, and
  Scios, Inc.
• W. Frank Peacock, MD, FACEP, of the Cleveland
  Clinic in Cleveland, Ohio reports no such
  relationships.

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Diabetes and Metabolic Syndrome in Patients
Hospitalized With CVD
Gregg C. Fonarow, MD
6
Polling Question 1
Do you screen for diabetes and metabolic syndrome
in patients hospitalized with an acute event
associated with cardiovascular disease?

• Yes, always
• Yes, most of the time
• No

7
AHA/NHLBI-Modified ATP III Criteria for the
Metabolic Syndrome
Risk Factor Defining Level Abdominal
obesity Waist circumference Men 40
in Women 35 in Triglycerides, mg/dL ?150 HDL-C,
mg/dL Men Hg ?130/85 Fasting glucose, mg/dL ?100 Lower
cutpoints for Asian Americans.
Diagnose by presence of 3 or more risk factors
Adapted with permission from Grundy SM, et al.
Circulation. 20051122735-2752.
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Metabolic SyndromePrevalence of Components

• Abdominal obesity 44
• Hypertriglyceridemia 33
• Low HDL cholesterol 40
• High blood pressure or medication use 39
• High fasting glucose or medication use 31

64 million US residents had the metabolic
syndrome in 2000
US adults aged 20 years and older (NHANES
1999-2000 data). Fasting plasma glucose ?100
mg/dL. Ford ES, et al. Diabetes Care.
2004272444-2449.
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1 in 4 Adults Have Diabetes or the Metabolic
Syndrome
Population at risk (millions)
Diagnosed diabetes
12
6.2
10
Undiagnosed diabetes
Prevalence, ,age 18 yrs
8
6
4
Diagnosed diabetes
14.6
2
0
White
Black
Hispanic
Other
35
Metabolic syndrome
30
Metabolic syndrome
64
25
Prevalence, ,age 20 yrs
20
15
10
5
0
White
Black
Hispanic
Other
2005 US data, NIDDK, NIH.Based on revised
NCEP/ATP III definition (NHANES 2000 data).
Mokdad AH, et al. JAMA. 200328976-79. Ford ES,
et al. JAMA. 2002287356-359. Ford ES, et al.
Diabetes Care. 2004272444-2449.
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Risk Factors Associated With the Metabolic
Syndrome (NHANES 1999-2000)
Metabolic syndrome
100
Without metabolic syndrome
90.9
77.0
80
73.9
73.9
60
Percentage
41.5
36.6
40
26.5
24.9
15.1
14.9
20
7.2
5.6
0
High BP
HighTriglycerides
High FastingGlucose
Low HDL-C
CVD History
High Waist Circumference
Adapted from Ford ES, et al. JAMA.
2002287356-359.
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Metabolic Syndrome Predicts Incidence of Diabetes
Independently of Impaired Glucose Tolerance
San Antonio Heart Study (N 1734 )
P 60
50
P .018
40
Diabetes,
P 30
20
10
Yes
Metabolic syndrome
No
0
No
Yes
Impaired Glucose Tolerance
ATP III definition.
Lorenzo C, et al. Diabetes Care.
2003263153-3156.
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Cardiovascular Disease Mortality and the
Metabolic Syndrome
Metabolic Syndrome
RR 3.55 (95 CI, 1.96-6.43)
Cumulative Hazard,
Controls
Metabolic Syndrome?
Follow-up, Years
866 288
852 279
834 234
292 100
Yes No
Based on factor analysis men in highest quarter
of distribution of the metabolic syndrome factor
were considered to have metabolic
syndrome.  Reproduced with permission from Lakka
HM, et al. JAMA. 20022882709-2716.
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Clustering of Risk Factors Increases Mortalityin
Post-CABG Patients 8-Year Follow-up
Obesity, Diabetes, Hypertension,
Hypertriglyceridemia
50454035302520151050
P risk factors to mortality
MenWomen
Mortality,
0
1
2
3
4
Number of Risk Factors
N 6428 deaths 860.
Sprecher DL, Pearce GL. J Am Coll Cardiol.
2000361159-1165.
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Overweight and Obesity Increase the Risk of
Cardiovascular Disease Mortality
3.0
2.6
2.2
Relative Risk of Cardiovascular Disease Mortality
1.8
1.4
1.0
Overweight
Normal weight
Obese
0.6
18 25 30
40
BMI, kg/m2
Data are from 1 million men and women (average
age, 57 years) followed for 16 years who never
smoked and had no history of disease at
enrollment. Calle EE, et al. N Engl J Med.
19993411097-1105.
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The Ticking Clock ? CV Risk Before ? Glucose
Nurses Health Study 20-year follow-up of
117,629 women
6
5.0
3.7
4
2.8
Relative risk ofMI or stroke
2
1.0
0
No diabetesthroughoutstudy
Risk of event prior to diabetesdiagnosis
Risk of eventafter diabetesdiagnosis
Diabetesat baseline
Hu FB, et al. Diabetes Care. 2002251129-1134.
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Association of Insulin Resistance With
Cardiovascular Risk Factors and Atherosclerosis
Central Obesity
Insulin resistance

• Impaired thrombolysis
• ? PAI-1
• ? tPA

Atherosclerosis
McFarlane SI, et al. J Clin Endocrinol Metab.
200186713-718.
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Waist Circumference Correlates With BP and
Insulin Resistance
768 men with fasting glucose 126 mg/dL (7
mmol/L)
High blood pressure
Insulin resistance
50
50
40
40
30
30

20
20
10
10
0
0
Quintiles of Waist Circumference
P Siani A, et al. Am J Hypertens. 200215780-786.
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Link Between Hyperglycemia and Poor Hospital
Outcomes
Metabolic stress response
? Stress hormones and peptides
? Glucose
? Insulin

• ? FFA
• ? Ketones
• ? Lactate

Immune dysfunction
? Reactive O2 species
? Transcription factors
Infection dissemination
? Secondary mediators
Cellular injury/apoptosis Inflammation Tissue
damage Altered tissue/wound repair Acidosis Infarc
tion/ischemia
Prolonged hospital stay
Disability
Death
Clement S et al. Diabetes Care. 200427553-591.
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Increasing Glucose Levels Increase Long-Term
Mortality in ACS
OPUS-TIMI 16 trial 10,288 patients with ACS
1 .95 .9 .85
Cumulative Survival
Quartile 1mg/dL Quartile 3120.6157 mg/dL Quartile 4157
mg/dL
P for trend across group0.006
0
100
200
300
Days of Follow-up
Bhadriraju S, et al. Am J Cardiol.
2006971573-1577.
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Hyperglycemia Increases In-Hospital Complications
and Long-Term Mortality
N2,127 patients with AMI or unstable angina1
Cooperative Cardiovascular Project N141,680
elderly patients hospitalized with AMI2
One-Year Mortality
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
P Diabetes No
Mortality Rate
Diabetes Yes
70
120
170
220
270
320
370
Q 15.8 mmol/L Q2 7.2 Q310.0 Q410.0.
Glucose (mg/dl)
1. Foo K, et al. Heart. 200389512-516. 2.
Kosiborod M, et al. Circulation.
20051113078-3086.
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Inpatient Management of Hyperglycemia and
Diabetes
American College of Endocrinology Task Force on
Inpatient Diabetes and Metabolic Control

• Values above 180 mg/dL are an indication to
  monitor glucose levels more frequently to
  determine need, if any, for more intensive
  intervention
• Targets for non-ICU patients are supported only
  by prospective observational studies
• Separate targets for pregnant patients (not shown)

American College of Endocrinology. Endocr Pract.
20041077-82.
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Inpatient Management of Metabolic Syndrome

• Evaluate all patients with hyperglycemia for
  metabolic syndrome
• Patients with hyperglycemia but no diabetes
  diagnosis during hospitalization should receive a
  written plan for follow-up testing after
  discharge
• Treatment of the metabolic syndrome often
  requires more than one pharmacotherapeutic agent
  for each component
• Interventions aimed at reducing the burden of
  obesity in the US would reduce the risk for
  metabolic syndrome

Selig PM. AACN Clin Issues. 20061779-85.
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Management of Cardiovascular Risk in Patients
With Abdominal Obesity
Abdominally obesepatient at increasedcardiometab
olic risk
Coronary heart disease
Risk factors

Hypertension
Dyslipidemia
Type 2 diabetes
Managecoronary heartdisease risk
Treat the complications?
Treat the cause
Adapted with permission from Després JP, et al.
BMJ. 2001322716-720.
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Effect of Interventions on Weight Change andRisk
of Diabetes and Metabolic Syndrome
Diabetes Prevention Program
Risk of developing metabolic syndrome
PB (n 1082)
LS (n 1079)
MET (n 1073)
MET
LS
0
0
-0.1
-2.1
-2
Weight Change, kg
-10
-4
-5.6
P -20
-17
Reduction in Risk of Metabolic Syndrome,
-6
-30
-8
MET
LS
-40
n1523
-41
-20
-50
-31
Reduction in Incidence of Diabetes
-40
P -58
P -60
LS lifestyle intervention MET metformin PB
placebo.
Orchard TJ, et al Diabetes Prevention Program
Research Group. Ann Intern Med. 2005142611-619.
Knowler WM, et al Diabetes Prevention Program
Research Group. N Engl J Med. 2002346393-403.
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Current Approaches to Treating Obesity

• Diet, exercise, and behavioral therapy continue
  to be the mainstays of obesity treatment
• Short-term efficacy of pharmacotherapy has been
  noted in clinical trials
• Side effects of pharmacologic therapy vary and
  may impact administration
• Surgery is reserved for morbidly obese patients
  with comorbidities

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Most Widely Prescribed Drugs for Treating Obesity
Approved for OTC use in January 2006. Adapted
from Yanovski SZ, Yanovski JA. N Engl J Med.
2002346591-602.
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Current Therapies Often Address Individual Risk
Factors
? Waist circumference ? Blood pressure ? Blood
glucose ? Triglycerides ? HDL-cholesterol ?
LDL-cholesterol Insulin resistance ? Thrombotic
risk
NCEP ATP IIIdefinitionof themetabolicsyndrome
Lipid modifiers
Insulin sensitizers
Antiplatelet agents
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Rimonabant, the First CB1 BlockerMay Affect
Multiple Targets

Rimonabant
Central
Peripheral
Brain
Adipocyte
CB1
CB1

• Adiponectin
• ? Insulin resistance
• ? Triglycerides
• ? Glucose tolerance
• ? HDL cholesterol

? Food intake
Weight loss
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Rimonabant In Overweight/Obesity Trials
Design
Population
Study
N
11 year Re-randomized
3045
Obese or overweightwith/without comorbidities
(except diabetes)
RIO-North America
2 years
1507
Obese or overweightwith/without comorbidities
(except diabetes)
RIO-Europe
1 year
1036
Obese or overweight withuntreated
dyslipidemia (diabetes excluded)
RIO-Lipids
1 year
1045
Obese or overweight withtype 2 diabetes
RIO-Diabetes
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Placebo-subtracted Change in Metabolic Syndrome
Parameters in 4 Rimonabant Trials
Mean ( SEM)
Waist Circumference, cm
HDL Cholesterol,



0

10
8.9
8.4
-1
8.1
5
7.2
-2
0
-3.3
cm
-3.6
-3
-5

P -4.2

-4
-10
-4.7


-15
-5
P
-20
-6
10
0.5
Triglycerides,
Systolic Blood Pressure, mm Hg
5
0
-0.2
-0.5
0
-1.2
-1

mm Hg
NS
-5
-1.7
-1.5
-12.4
-10
NS
-13.2
-2.3
-15.1
-2
-16.4
-15

P
-2.5


-20
P -3
P N 6600 ITT, LOCF

• 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 AF. Presented at 65th Annual Scientific
  Sessions of the ADA June 12, 2005 San Diego,
  Calif.

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RIO-North America Change in Metabolic Syndrome
Status
34.8
31.7
40
Baseline
1-Year Treatment
30
29.2
20
Patients,
21.2
P 10
0
Placebo
Rimonabant 20 mg
ITT, LOCF
Pi-Sunyer FX, et al. JAMA. 2006295761-775.
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Pooled RIO Studies Overall Safety
RIO- North America
RIO- Europe
RIO- Lipids
RIO- Diabetes
RIO- North America
RIO- Europe
Year 1
Year 2
Placebo
Placebo
Rimonabant5 mg
Rimonabant20 mg
Rimonabant20 mg
Rimonabant5 mg
(n 663)
(n 688)
(n 2503)
(n 2520)
(n 466)
(n 1602)
Subjects with any adverse event
77.0
74.4
76.7
86.0
82.9
81.8
Subjects with any serious adverse event
5.4
4.7
4.5
5.9
5.4
4.2
4.7
4.5
4.7
13.8
8.8
7.2
Subjects discontinued due to adverse event
Includes all deaths occurring in all four RIO
studies4 on placebo, 3 on rimonabant 5 mg, 4 on
rimonabant 20 mg.
Scheen A, et al. Presented at American Diabetes
Association 65th Annual Scientific Sessions June
12, 2005 San Diego, Calif.
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Summary

• The prevalence of obesity and diabetes is
  increasing dramatically
• Metabolic syndrome, a precursor to CVD and
  diabetes, also is increasing dramatically
• Obesity is a major risk factor for diabetes and
  CVD, and the driving force behind the metabolic
  syndrome
• Weight reduction and exercise are the cornerstone
  of cardiometabolic risk reduction
• Pharmacotherapy can be used along with lifestyle
  intervention to reduce cardiometabolic risk
  factors

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Featured Institution
Cleveland Clinic Foundation Cleveland, Ohio
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Polling Question 2
If you participated in a previous teleconference,
how much progress have you made since
then? (Please refer to the checklists on the next
3 slides.)

• We are currently on the same item
• We have since moved to the next checkbox on the
  checklist
• We have progressed by more than one item on the
  checklist
• ACS pathways are up-to-date and regularly
  followed

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Progress ChecklistImmediate Goals
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Progress ChecklistShort-term Goals/Activities
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Progress ChecklistLong-term Goals/Activities
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Question-and-Answer Session
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Concluding RemarksGregg C. Fonarow, MD
Next Program Highlights From the 2006
Transcatheter Cardiovascular Therapeutics (TCT)
ConferenceChristopher P. Cannon, MDWednesday,
November 8, 20061200 Noon Eastern Time (900
AM Pacific Time)