Diabetes, Obesity, Cardiovascular Dz A Combined Collaborative

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Diabetes, Obesity, Cardiovascular Dz
A Combined Collaborative

• Stephan Babirak,PhD,MD
• Learning Session 1

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The Blind Men and The Elephant John
Godfrey Saxes version of a Chinese Parable
(202 BC-220 AD)

• Side Wall
• Tusk Spear
• Trunk Snake
• Knee Tree
• Ear Fan
• Tail Rope

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The Blind Men and the Elephant

• So oft in theologic (medical) wars,
• The disputants, I ween,
• Rail on in utter ignorance
• Of what each other mean,
• And prate about an Elephant
• Not one of them has seen!

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Medical Complications of Obesity
Idiopathic intracranial hypertension
Pulmonary disease abnormal function obstructive
sleep apnea hypoventilation syndrome
Stroke
Cataracts
Nonalcoholic fatty liver disease steatosis steatoh
epatitis cirrhosis
Coronary heart disease Diabetes
Dyslipidemia Hypertension
Severe pancreatitis
Gall bladder disease
Cancer breast, uterus, cervix colon, esophagus,
pancreas kidney, prostate
Gynecologic abnormalities abnormal
menses infertility polycystic ovarian syndrome
Osteoarthritis
Phlebitis venous stasis
Skin
Gout
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Increase in Healthcare Costs Among Obese Compared
with Lean (BMI Increase in Cost Compared with Lean Subjects ()
BMI 30-34 kg/m2
BMI 35 kg/m2
HMO Setting Northern California Kaiser
Permanente.
Quesenberry CP Jr et al. Arch Intern Med.
1998158466-472.
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Direct Cost of Chronic Diseases in the United
States
53.2
51.6
38.7
Direct Cost ( Billions)
18.4
18.1
Type 2Diabetes
Obesity
CoronaryHeart Disease
Hyper-tension
Stroke
Adjusted to 1995 dollars.
Wolf AM, Colditz GA. Obes Res. 1998697-106. Hodg
son TA, Cohen AJ. Med Care. 199937994-1012.
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Diabetes and Obesity are linked
Diabetes
Mean body weight

• Prevalence of obesity, increased by 61 since
  1991
• More than 50 of US adults are overweight
• BMI and weight gain major risk factors for
  diabetes

kg
Prevalence ()
Year
Mokdad et al. Diabetes Care. 2000231278. Mokdad
et al. JAMA. 19992821519. Mokdad et al. JAMA.
20012861195.
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Relationship Between BMI and Risk of T2DM
93.2
Men Women
54.0
Age-Adjusted Relative Risk
42.1
40.3
27.6
21.3
15.8
8.1
5.0
11.6
4.3
2.9
2.2
6.7
4.4
1.5
1.0
1.0
1.0
Body Mass index (kg/m2)
Chan J et al. Diabetes Care 199417961. Colditz
G et al. Ann Intern Med 1995122481.
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Major Risk Factors for Type 2 Diabetes

• Family history (eg, parents or siblings with
  diabetes)
• Overweight (BMI ? 25 kg/m2), 80 are
  obese/overweight
• Habitual physical inactivity
• Race/ethnicity (eg, African Americans, Hispanic
  Americans, Native Americans, Asian Americans, and
  Pacific Islanders)
• Previously identified IFG or IGT
• Hypertension (? 140/90 mm Hg in adults)
• HDL cholesterol ? 35 mg/dL and/or TG ? 250 mg/dL
• History of GDM or delivery of a baby weighing 9
  lbs
• Polycystic ovary syndrome

American Diabetes Association. Diabetes Care.
200225(suppl 1)S21-S24.
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Diabetes is a Cardiovascular Disease

• 10-year risk for CHD ? 20
• High mortality with established CHD
• High mortality with acute MI
• High mortality post acute MI

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Risk of Both Macrovascular and Microvascular
Complications Increases With Higher A1C
MI
Adjusted incidence/1000 person-y ()
5
6
7
8
9
10
11
Updated mean A1C concentration ()
Stratton et al. BMJ. 2000321405.
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Fasting Glucose, 2-Hour Postchallenge Glucose,
and Mortality in Individuals Not Known as
Diabetic DECODE Study
2.50
2.00
1.50
Hazard Ratio for Death
1.00
? 200
0.50
140-199
2-Hour Glucose(mg/dL)
0.00
140
Fasting Glucose (mg/dL)
Adjusted for age, sex, and study center.DECODE
Diabetes Epidemiology Collaborative Analysis
of Diagnostic Criteria in Europe. DECODE Study
Group. Lancet. 1999354617-621.
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Stepwise of Risk Factors in UKPDS

• Coronary heart disease (n 280)
• Position in model Variable P value
• 1st LDL-C
• 2nd HDL-C 0.0001
• 3rd Hemoglobin A1c 0.0022
• 4th Systolic blood pressure 0.0065
• 5th Smoking 0.056

Turner RC et al. BMJ 1998316823828
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Epidemiology Overweight and Obesity

• According to the CDC, in 19992000
• Nearly one third of adult Americans were obese
  (60 million).1
• 64.5 of adult Americans were overweight or
  obese (127 million).1
• In 2000, approximately 112,000 excess deaths were
  associated with obesity in the United States.2

1. CDC, National Center for Health Statistics,
National Health and Nutrition Examination Survey.
Health, United States, 2002. 2. Flegal et al.
JAMA. 200529318611867. 3. Flegal KM et al.
JAMA. 200228817231727. 4. NHLBI. Clinical
Guidelines on the Identification, Evaluation and
Treatment of Overweight and Obesity in Adults,
1998.
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Cardiovascular Disease and Obesity



Men Women
Relative Risk of Death
Lean
Overweight
Obese
18.520.4
20.521.9
22.0 23.4
23.5 24.9
25.0 26.4
26.527.9
28.0 29.9
30.0 31.9
32.034.9
35.0 39.9
40.0
Body Mass index
Calle et al. N Engl J Med 19993411097.
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Categories of Cardiovascular Risk Factors

• Major, independent risk factors
• Life-habit risk factors
• Emerging risk factors

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Major Risk Factors (Exclusive of LDL
Cholesterol) That Modify LDL Goals

• Cigarette smoking
• Hypertension (BP ?140/90 mmHg or on
  antihypertensive medication)
• Low HDL cholesterol (
• Family history of premature CHD
• CHD in male first degree relative
• CHD in female first degree relative
• Age (men ?45 years women ?55 years)

HDL cholesterol ?60 mg/dL counts as a
negative risk factor its presence removes one
risk factor from the total count.
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Life-Habit Cardiovascular Risk Factors

• Obesity (BMI ? 30)
• Physical inactivity
• Atherogenic diet

22
Emerging Cardiovascular Risk Factors

• Lipoprotein (a)
• Homocysteine
• Prothrombotic factors
• Proinflammatory factors
• Impaired fasting glucose
• Subclinical atherosclerosis

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Prevalence of Metabolic Disorders in the General
Population by BMI Category
US Survey of 195,005 Adults in 2001
BMI
?40
of US adults
Mokdad et al. JAMA 200328976.
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New Features of ATP III

• Focus on Multiple Risk Factors
• Diabetes CHD risk equivalent
• Framingham projections of 10-year CHD risk
• Identify certain patients with multiple risk
  factors for more intensive Rx
• Multiple metabolic risk factors (metabolic
  syndrome)
• Intensified therapeutic lifestyle changes

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Adipose Tissue as an Endocrine Organ
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Leptin

• Modulates energy homeostasis, true hormone
  secreted from adipocytes to receptors in Arcuate
  Nucleus of Hypothalamus
• ? with adipose tissue mass - causes satiety,
  stimulates EC,,angiogenesis, wound healing,
  suppresses cortisol
• Low levels a/w increased appetite, decreased
  energy expenditure, gonadotropins, reproductive
  function, thyroid function, immune function,
• Deficiency/Resistence

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Adiponectin- inverse relationship with Obesity,
Diabetes and CHD

• Liver
• ? Insulin sensitivity
• ? Influx of fatty acids
• ? Fatty acid oxidation
• ? Glucose output
• Muscles
• ? Fatty acid oxidation

• Vascular Wall
• ? monocyte adhesion
• ? macrophage transformation to foam cells
• ? VSMC proliferation
• ? NO production
• ? angiogenesis

Guerre-Millo M. Diabetes Metab 2004 30 13.
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Abdominal Fat Distribution Increases the Risk of
Coronary Heart DiseaseThe Iowa Womens Health
Study
Relative risk
Waist-HipRatioTertile
3
2
1
2
1
3
Body Mass Index Tertile
Folsom et al. Arch Intern Med 20001602117.
36
Waist Size vs BMI and the Metabolic Syndrome
Waist circumference circumference level 2
33.43
8-y Incidence of Metabolic Syndrome ()
20.45
19.77
9.98
Level 2 waist ?40 inches in men or ?35 inches
in women.
Han TS et al. Obes Res. 200210923-931.
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IL-6

• Stimulates hepatic production of CRP
• Highly correlated to body mass
• Inversely related to insulin sensitivity
• Alters insulin signaling in hepatocytes

Guerre-Millo M. Diabetes Metab 2004 30 13.
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TNF-?

• Overexpressed in adipose tissue
• ? Insulin resistance
• ? Endothelial dysfunction
• ? CRP
• ? IL-6
• ? PAI-1
• ? adiponectin

Guerre-Millo M. Diabetes Metab 2004 30 13.
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Angiotensinogen

• Mainly produced by liver but adipose tissue is a
  major extrahepatic source
• Promotes hypertension
• ? adipose tissue mass

Guerre-Millo M. Diabetes Metab 2004 30 13.
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PAI-1

• Promotes thrombus formation by inhibiting
  fibrinolysis
• Elevated levels associated with visceral
  adiposity
• May affect adipose tissue growth

Guerre-Millo M. Diabetes Metab 2004 30 13.
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Major Risk Factors (Exclusive of LDL
Cholesterol) That Modify LDL Goals

• Cigarette smoking
• Hypertension (BP ?140/90 mmHg or on
  antihypertensive medication)
• Low HDL cholesterol (
• Family history of premature CHD
• CHD in male first degree relative
• CHD in female first degree relative
• Age (men ?45 years women ?55 years)

HDL cholesterol ?60 mg/dL counts as a
negative risk factor its presence removes one
risk factor from the total count.
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Emerging Cadrdiovascular Risk Factors

• Lipoprotein (a)
• Homocysteine
• Prothrombotic factors
• Proinflammatory factors
• Impaired fasting glucose
• Subclinical atherosclerosis

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Medical Benefits of Modest Weight Loss
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Insulin Sensitivity Improves with Weight Loss in
Patients with Type 2 Diabetes


Insulin (pmol/L)

Before
0-2.4
2.5-6.9
7.0-14.0
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Weight Loss at 1 Year ()
PWing et al. Arch Intern Med 19871471749.
46
Prevention of Type 2 Diabetes Completed Trials
in IGT
Results
Description
Journal/Yr
trial
Diabetes Care/1997
Diet /or exercise
3146 risk reduction
Da Qing
Intensive lifestyle
58 risk reduction
NEJM/2001
FPS
DPP
31 risk reduction 58 risk reduction
Metformin lifestyle
NEJM/2002
25 risk reduction
Acarbose
Lancet/2002
STOP-NIDDM
1. Pan XR et al. Diabetes Care. 199720537544.
2. Tuomilehto J et al. N Engl J Med.
200134413431350. 3. Knowler WC et al. N Engl J
Med. 2002346393403. 4. Chiasson JL et al.
Lancet. 200235920722077.
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Plasma Lipids Improve with Weight Loss
Meta-analysis of 70 Clinical Trials
TG
HDL-C(weightstable)
HDL-C(activelylosing)
TotalCholesterol
LDL-C



? mmol/L kg of Weight Loss

? mg/dL per kg of Weight Loss

PLDL-Clow density lipoprotein cholesterol
HDL-Chigh-density lipoprotein cholesterol
TGtriglycerides
Dattilo et al. Am J Clin Nutr 199256320.
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Relationship Between Change in Weight and Blood
Pressure Trials of Hypertension Prevention II
Diastolic
Systolic
Change in BloodPressure (mm Hg)
Quintile of Weight Change
Change in Weight (kg)
Stevens et al. Ann Intern Med 20011341.
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Impact of Weight Loss on Risk Factors
1
1
2
2
3
3
3
3
4
1. Wing RR et al. Arch Intern Med.
19871471749-1753. 2. Mertens IL, Van Gaal LF.
Obes Res. 20008270-278. 3. Blackburn G. Obes
Res. 19953 (Suppl 2)211S-216S. 4. Ditschunheit
HH et al. Eur J Clin Nutr. 200256264-270.
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Relationship Between Weight Change and CHD Risk
Factor Sum Framingham Offspring Study
Weight Change During 16-y Follow-up

Loss 2.25 kg
Gain 2.25 kg
37

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Change in Risk Factor Sum ()


-40
-48
Men
Women
PWilson et al. Arch Intern Med 19991591104.
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Obesity and Exercise
52
Physical Activity Alone Results in Minimal Weight
Loss
Control Group Exercise Group
Stefanick 1998 Stefanick 1998a Anderssen
1995 Hammer 1989 Verity 1989 Rönnemaa 1988 Wood
1988 Wood 1983




Weight loss (kg)
PDuration of each study ranged from 4 to 12 months.
Wing. Med Sci Sports Exerc 199931(suppl)S547.
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Physical Activity Usually Does Not Increase
Short-Term Diet-Induced Weight Loss
Wadden 1997 Ross 1996 Marks 1995 Ross 1995 Blonk
1994 Sweeney 1993 Bertram 1990

Weight loss (kg)
PEach study ranged from 4 to 6 months.
Wing RR. Med Sci Sports Exerc. 199931(suppl)S547
-S552.
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Relationship Between Physical Activity and
Maintenance of Weight Loss
PSubjects Exercising ()
Not Maintained
Maintained
Weight Loss Pattern
Kayman et al. Am J Clin Nutr 199052800.
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Considerable Physical Activity is Necessary for
Weight Loss Maintenance
Concomitant Behavior Therapy
Weekly
Biweekly
Monthly
Change in Weight (kg)
150 min/wk
P200 min/wk
0
6
12
18
Time (months)
Jakicic et al. JAMA 19992821554.
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Obesity and Dietary Therapy Duct Tape
57
Short-term Obesity Therapy Does Not Result in
Long-term Weight Loss
Diet alone Behavior therapy Combined therapy
Change in Weight (kg)
5-yearFollow-up
1-yearFollow-up
End ofTreatment
Baseline
Wadden et al. Int J Obes 198913 (Suppl 2)39.
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Sustained Weight Loss Can Be Achieved with
Behavior Modification Therapy
No Active Treatment
Active Treatment
Women
Weight Loss (kg)
Men
0
2
4
6
8
10-12
Years
Björvell and Rössner. Int J Obes Relat Metab
Disord 199216623.
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Obese Patients Have Unrealistic Weight Loss Goals
Foster et al. J Consult Clin Psychol 19976579.
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Cardinal Behaviors of Successful Long-term Weight
ManagementNational Weight Control Registry Data

• Self-monitoring
• Diet record food intake daily, limit certain
  foods or food quantity
• Weight check body weight 1 x/wk
• Low-calorie, low-fat diet
• Total energy intake 1300-1400 kcal/d
• Energy intake from fat 20-25
• Eat breakfast daily
• Regular physical activity 2500-3000 kcal/wk
  (eg, walk 4
  miles/d)

Klem et al. Am J Clin Nutr 199766239. McGuire
et al.Int J Obes Relat Metab Disord 199822572.
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Regulation of Food Intake
Brain
Central Signals
Stimulate
Inibit
NPY AGRP galanin
Orexin-A Dynorphin CB-1
a-MSH CRH/UCN GLP-I
CART NE 5-HT
Peripheral signals
Peripheral organs
Glucose CCK, GLP-1,Apo-A-IVVagal
afferents Insulin GhrelinLeptinCortisol
Gastrointestinaltract
FoodIntake
Adiposetissue
Adrenal glands
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Principles of Pharmacotherapy in the Management
of Obesity
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Drugs Approved by FDA for Treating Obesity
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Regulation of Food Intake
Brain
Central Signals
Stimulate
Inibit
NPY AGRP galanin
Orexin-A Dynorphin CB-1
a-MSH CRH/UCN GLP-I
CART NE 5-HT
Peripheral signals
Peripheral organs
Glucose CCK, GLP-1,Apo-A-IVVagal
afferents Insulin GhrelinLeptinCortisol
Gastrointestinaltract
FoodIntake
Adiposetissue
Adrenal glands
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Gastrointestinal Peptides Hormones
food intake regulation
Anti-obesity potential
digestion and metabolism
Anti-diabetes potential
Modified from Marx, Science 2003 February 7 299
846-849. (in News)
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GLP-1

• GLP-1 incretin hormone
• Exenatide (Byetta) incretin mimetic
• Enhances insulin secretion
• Suppresses elevated glucagon secretion
• Reduces food intake and body weight
• Slows gastric emptying
• Increase in beta-cell mass

Toft-Nielsen M, et al. J Clin Endocrinol Metab
2001 863717-3723 Drucker DJ. Mol Endocrinol
2003 17161-171 Nielsen LL, et al. Reg Pept
2004 11777-88
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Neuroendocrinology of Food Intake
RegulationHindbrain as a Target for Peripheral
Satiety Signals
Hypothalamus
ARC
NTS/AP
Vagus
Spinalnerves
CCK
GI tract
Leptin Insulin
PYY
Ghrelin
Amylin other circulating gut peptides
Modified from Marx, Science 2003 February 7 299
846-849. (in News)
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Progressive Weight Reduction inExenatide-Treated
T2DM Patients
Open-Label Extensions
Placebo-Controlled
Baseline weight 100 kg
0
No special diet or exercise
counseling was provided
-2
D Weight (kg)
-4
-4.6 0.4 kg
-6
20
40
60
80
0
Duration of Treatment (wk)
N 265 Mean (SE)
70
Safety and Tolerability Exenatide Open-Label
Extensions

• Exenatide generally well tolerated
• Adverse events
• Nausea (30-40)
• Diarrhea (7)
• Vomiting (9)
• Feeling jittery (5)
• Dizziness (3)
• Headache (3)

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AmylinA Neuroendocrine Hormone
Amylin ReceptorIdentified
N
N
Amylin Binding Sites in the Brain
Dorsale Raphe
C
C
RAMP 1 or 3
CTR
Nucleus Accumbens
Area Postrema
Beaumont K, et al. Mol Pharm 1993
44493-497 Adapted from Muff R, et al.
Endocrinology1999 1402924-2927
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Effects of Pramlintide in Type 2 Diabetes
Pooled 120 µg BID Pramlintide Intent to Treat
Populations
Change in Insulin Use ()
Change in A1C ()
Change in Weight (lb)
Week 4
Week 13
Week 26
Week 4
Week 13
Week 26
Week 4
Week 13
Week 26
2.5
6
0
2.0
5
-0.1
1.5
4
-0.2
1.0
3
0.5
-0.3
2
0
-0.4
-0.5
1
-0.5
-1.0
0
-1.5
-0.6
-1
-2.0
-0.7
-2
-2.5
-3
-0.8
-3.0
Data on file, Amylin Pharmaceuticals, Inc.
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Endocannabinoid System (ECS)

• CB1 receptor- activated by endogenous
  cannabinoids and overactive in obesity
• Present in CNS (hypothalamus limbic system),
  adipocyte, liver, EC, pancreas, muscle, GI tract
• Rimonabant is CB1 receptor antagonist- appetite
  suppressant and reduces body weight, tobacco and
  Etoh dependance

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RIO-DIABETESStudy Design
Screening
600 kcal/day energy deficit diet
Placebo n348
n231
Placebo
Rimonabant 5 mg/day n358
n232
Single-blind
n229
Rimonabant 20 mg/day n339
Week - 6
Week 0
Week - 4
Week 52
Scheen A. Late Breaking Clinical Trials. ADA
Scientific Session 2005.
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RIO-DIABETESResults Weight Changes
Scheen A. Late Breaking Clinical Trials. ADA
Scientific Session 2005.
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Weight Changes in RIO-Europe at Two Years
Intention-to-treat analysis
Van Gaal L. American College of Cardiology 2005
Scientific Sessions March 6-9, 2005 Orlando, FL.
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Conclusions

• Obesity is a chronic disease
• Modest weight loss (5 -10 of body weight) can
  have considerable medical benefits
• Lifestyle change (diet and physical activity) is
  the cornerstone of therapy
• Pharmacotherapy can be useful in properly
  selected patients
• Bariatric surgery is the most effective therapy
  for severe obesity