Transcript “Obesity and Chronic Diseases” Colorado Center for Health Wellness National Press Foundation April 29, 2013 Robert H.

“Obesity and Chronic
Diseases”
Colorado Center for Health Wellness
National Press Foundation
April 29, 2013
Robert H. Eckel, M.D.
Professor of Medicine
Professor of Physiology and Biophysics
Charles A. Boettcher II Chair in Atherosclerosis
University of Colorado Anschutz Medical Campus
[email protected]
Medical Complications of Obesity
Pulmonary disease
abnormal function
obstructive sleep apnea
hypoventilation syndrome
pulmonary embolism
Pulmonary hypertension
Nonalcoholic fatty liver
disease
steatosis
steatohepatitis
cirrhosis
Gall bladder disease
Gonadal abnormalities
abnormal menses
infertility
polycystic ovarian syndrome
erectile dysfunction
Osteoarthritis
Skin
Gout
Idiopathic intracranial hypertension
Stroke
Cognitive impairment
Cataracts
Coronary heart disease
CHF, arrhythmias
Diabetes
Hypertension
Dyslipidemia
Pancreatitis
Cancer
breast, uterus, cervix
colon, esophagus, pancreas
kidney, prostate, thyroid
Phlebitis
venous stasis
Eckel RH, NEJM 358:1941, 2008
Eckel RH, NEJM 358:1941, 2008
Obesity and Cancer: Meta-analysis –
221 Datasets from 1966-2007
Renehan AG et al, Lancet 371:569, 2008
RR of Cancer in Men with a
5 Kg/m2 Increase in BMI
- 282,137 incident cases
Renehan AG et al, Lancet 371:569, 2008
RR of Cancer in Women with a
5 Kg/m2 Increase in BMI
- 126,804 incident cases
Renehan AG et al, Lancet 371:569, 2008
Obesity and a Strong RR (>1.2) of
Cancer
• Men
– Esophagus - adenoCa
– Thyroid
– Colon
– Renal
1.52
1.33
1.24
1.24
• Women
– Endometrial
– Gallbladder
– Esophageal - adenoCa
– Renal
1.59
1.59
1.51
1.34
Renehan AG et al, Lancet 371:569, 2008
T47D Cancer Cells Stained with Oil
Red O for Neutral Lipid
FDG PET Scans of Metastatic Prostate
Cancer before and 24 Hours after Fatty
Acid Oxidation is Blocked
Basal FDG-PET Scan
Etomoxir 24 hours
Obesity and Cancer
Screening
http://www.cancer.gov
Hypertension and Obesity:
NHANES III (1988-1994)
Brown CD et al, Obes Res 8:605, 2000
The Link Between Insulin Resistance
and Endothelial Dysfunction
Lipolytically Active
Abdominal Adipose
Tissue
IL-1, IL-6, TNFa
Vascular Endothelium
Vasodilation
Shear Stress
Inflammation
Atherosclerosis
Thrombosis
CRP
PAI-1
©
Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634.
Caballero AE. Obesity Res. 2003;11:1278-1289.
Mechanisms Relating Obesity to
Hypertension
Narkiewicz K et al Obes Rev 7:155, 2006
Ischemic Heart Disease Mortality vs
Usual BP by Age
Systolic Blood Pressure
256
IHD
mortality
(floating
absolute
risk and
95% CI)
Age (yr) at risk
80-89
Diastolic Blood Pressure
Age (yr) at risk
80-89
128
70-79
70-79
64
60-69
60-69
32
50-59
50-59
40-49
40-49
16
8
4
2
1
0
120 140 160 180
Usual systolic BP (mm Hg)
70 80 90 100 110
Usual diastolic BP (mm Hg)
.
Prospective Studies Collaboration. Lancet. 360:1903, 2002
BMI and Diabetes: A Large Effect!
Men
Women
6
6
5
5
4
4
3
3
2
2
1
1
0
<21 22 23 24 25 26 27 28 29 30
0
<21 22 23 24 25 26 27 28 29 30
BMI (kg/m2)
BMI, body mass index.
Willett WC et al. NEJM 341:427,1999
BMI (kg/m2)
Type 2 diabetes
Cholelithiasis
Hypertension
Coronary heart 23
disease
Risk for Development of T2DM
Effect of BMI in Women
100
90
80
Age-adjusted 70
RR(%) of
60
Developing
50
T2DM over 14
40
yr in women
aged 30-55 in 30
20
1976
10
0
2007
Overweight
34%
<22 22- 23- 24- 2523 24 25 27
Obese
31%
27- 29- 31- 33- >35
29 31 33 35
Attained BMI
NHS. Ann Int Med 122:481,
Natural History of T2DM:
A Critical Understanding
Glucose
(mg/dL)
350
300
250
200
150
100
Diabetes
Fasting
glucose
IGT
-15
Relative
Function
(%)
Post-meal
glucose
-10
-5
0
5
10
125
100
75
50
25
0
15
20
25
Insulin resistance
ß-cell
-15
-10
-5
0
5
10
Years of Diabetes
15
20
25
Pathogenesis: ß-Cell Compensation
and Decompensation and T2DM
Insulin Secretion (mU/mL)
b-Cell Failure
500
400
Normal Glucose
Tolerance
300
Impaired
Glucose
Tolerance
200
100
Type 2
Diabetes
0
0
1
2
3
4
5
Insulin Action (mg/kg EMBS per minute)
Insulin
Resistance
Weyer C et al. J Clin Invest 104: 787, 1999
DPP:Mean Weight Change from
Baseline
+1
0
-1
-2
-3
-4
-5
-6
-7
-8
Weight Change (Kg)
Placebo
Metformin
Lifestyle
4.2%
0
7.2%
N= 3051
2865
6
24
NEJM 2002;346: 393
12 18
1500
30
Months
36
385
42
48
DPP: Diabetes Prevention
Cumulative incidence (%)
All participants-2.8 years
Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
Metformin (n=1073, p<0.001 vs. Plac)
Placebo (n=1082)
40
30
20
10
0
0
1
2
3
Years from randomization
NEJM 346: 393, 2002
4
31%
58%
Diabetes incidence / 100 pers-yr
Diabetes Risk by Weight Change
in the DPP
16
Weight loss explained 64% of
the risk reduction from
metformin
(a weight loss drug?)
placebo
11
metformin
6
-10 -8
-6 -4 -2
0
2
Change from baseline weight (kg)
4
6
Diabetes 56:1153, 2007
Genetic Risk vs. Lifestyle in T2DM?
(TCF7L2 SNP)
Lifestyle intervention “trumps” genetic risk
Florez J et al, DPP Research Group, NEJM 355:241, 2006
Weight Loss in T2DM and Less CVD:
Did Look AHEAD Answer All the
Questions?
• Primary Objective – To assess the long-term
(11.5 yr) effects of an intensive weight loss
program over 4 years in overweight and
obese subjects with type 2 diabetes.
–
–
–
–
–
n ~ 5000 men and women
age: 45-74 yr
BMI > 25 kg/m2
Primary outcome – time to a major CVD event
Secondary outcomes - many
Controlled Clin Trials 24:610, 2003
Percentage of Participants in ILI and DSE
Groups Who Met Different Weight Loss
Criteria at Year 4
100
Intensive Lifestyle Intervention (ILI)
90
Diabetes Support & Education (DSE)
% of Participants
80
74%
70
60
55%
50
46%
45%
40
35%
30
26%
20
10
25%
18%
18%
23%
10%
8%
9%
4%
0
≥5%
≥ 0%
Weight Gain
>0%
≥5%
≥7%
≥ 10 %
≥ 15 %
Weight Loss
Look AHEAD Research Group, 2011
Change in body weight (%)
4-Year Weight Loss Outcomes
0
-1
-2
-3
-4
*
Overweight
Class I
Class II
Severe
-5
-6
* Overweight significantly different from all other groups (p<0.001)
Look AHEAD Research Group, 2011
Revised NCEP ATP III LDL-C Goals
CHD Risk
Category
High
(Very High)
Moderately High
Moderate
Low
Circulation 2004; 110: 227
CHD or Risk
Equivalent
(>20%/10 yr)
2+ RF
(10-20%/10 yr)
2+ RF
(<10%/10 yr)
0–1 RF’s
LDL-C
Goal
Consider
Drug Rx
<100
100*
(<70)
<130
130*
<130
160*
<160
190*
* Consider drug options if below goal,
but above goal for next higher risk level
Metabolic Syndrome:
• April 2008
Residual Risk
– Known CHD
• On a statin
–
–
–
–
LDL-C 67 mg/dl
TG 300 mg/dl
HDL-C 32 mg/dL
ETT – normal
• June 2008
– AMI at work
• Resuscitation failed
• Could this have been
Grady D. A Search for Answers in Russert’s Death. The New York
avoided?
Times. June 17, 2008.
The New Definition of The Metabolic
Syndrome (3 or more)
Approved by NHLBI, AHA, IDF, IAS, World Heart Federation
• Abdominal circumference (1 of 5)
– men > 94 cm
– women > 84 cm
• adjusted locally around the world
• Triglycerides > 150 mg/dl
• HDL cholesterol
– men < 40 mg/dl
– women < 50 mg/dl
• Blood pressure > 130/85
• Glucose > 100 mg/dl
Eckel RH et al, Lancet, 375:181, 2010
39
Metabolic Syndrome is Designed for
Lifestyle Intervention
• An intervention that improves the quality of
the diet, increases physical activity and
produces weight reduction often 
–
–
–
–
–
–
 waist circumference (+  visceral fat)
 triglycerides
 HDL cholesterol
 blood pressure
 glucose
 inflammatory markers
Fatty Liver (Foie Gras)
Goose liver after 3 months of
overfeeding and inactivity
Normal goose liver
Definition: NAFLD & NASH
• NAFLD = Non-Alcoholic Fatty Liver Disease
– Spectrum includes
• Steatosis
• Steatohepatitis
• Fibrosis and cirrhosis
• NASH = Non-Alcoholic Steatohepatitis
– Histological diagnosis
• Necro-inflammation
• Fibrosis
• Cirrhosis
– Histology similar to alcoholic hepatitis
Pathogenesis of NAFLD
-Neuschwander-Tetri, Hepatology, 2002
Pathogenesis of NAFLD
“first hit”
-Neuschwander-Tetri, Hepatology, 2002
Pathogenesis of NAFLD
“second hit”
-Neuschwander-Tetri, Hepatology, 2002
Prevalence of NAFLD
Steatosis
20-30% US adults
60% of obese adults
-Neuschwander-Tetri, Hepatology,
2002
-McCullough AJ. NAFLD:
AASLD Symposium, Nov 9 2001
Prevalence of NAFLD
NASH 2-3% US adults
20-25% of obese adults
-Neuschwander-Tetri, Hepatology,
2002
-McCullough AJ. NAFLD:
AASLD Symposium, Nov 9 2001
Cirrhosis and NAFLD
-Neuschwander-Tetri,
Hepatology, 2002
-McCullough AJ. NAFLD:
AASLD Symposium, Nov 9
2001
2-3% of obese adults
Who should be
screened for NAFLD?
Patients at Higher Risk for NASH
• Obese (BMI > 30 kg/m2)
– BMI > 25 < 30 kg/m2
•
•
•
•
•
•
•
Diabetes mellitus (Type 2)
HOMA > 1.64 (More insulin resistant)
Family History
Age > 50 yr
Males > females
Hispanic > White > Black
Metabolic syndrome
Important Caveat
Standard blood tests for liver
disease, may be completely
normal in many patients with
NAFLD:
Even patients with NASH or
advanced fibrosis due to
NASH!!!!
Abrams G, et al. Hepatology 2004;40:475
Obstructive Sleep
Apnea-Hypopnea Syndrome
•
•
•
•
•
•
•
•
•
•
Snoring
Severe sleepiness
Restless sleep
Night sweats
Morning dry mouth/sore throat
Nocturia
Morning headaches
Erectile dysfunction
Morning confusion
Personality change
Approach to the Obese Patient
with Suspected OSAH
ANC = Adjusted
Neck Circ
De Souza AGP et al, Obes Rev 10:1467, 2008
CVD Mortality and Obesity:
Cancer Prevention Study II
Relative Risk of Death
3.0
Men (n=84,376)
Women (n=217,857)
2.6
Non-smokers
Without known heart disease
2.2
1.8
1.4
1.0
0.6
<18.5
22
25
28 30
Body Mass Index (BMI)
35
Calle EE et al. NEJM 341:1097,1999
Metabolic Pathophysiology
of Obesity and CVD
• Hypertension
• Dyslipidemia
• Inflammation
• Diabetes
Incidence rate per 100,000
person-years
Abdominal Obesity and Coronary Heart
Disease in Women: The Nurses’ Health Study
128
Follow-up of 8 years
110
140
106
120
97
89
Waist Girth
Tertiles (cm)
100
80
77
60
83
46
55
High (81.8 - <139.7)
40
Middle (73.7 - <81.8)
20
Low (38.1 - <73.7)
0
High
(25.2 - <48.8)
Middle
(22.2 - <25.2)
Low
(12.2 - <22.2)
Body Mass Index Tertiles (kg/m2)
Adapted from Rexrode KM et al. JAMA 280: 1843, 1998
Mean Value of Log CRP
CRP by Number of Metabolic Disorders
(Dyslipidemia, Upper Body Adiposity, Insulin
Resistance, Hypertension)
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0
1
2
3
4
Number of Metabolic Disorders
Festa et al. Circulation 102:42, 2000
Hazard Ratio for the Risk of Diabetes
Over 17 Years in Healthy Young Adults, According
to BMI in Adolescence and in Adulthood
37,674 young men, Staff Periodic Exam,
Israeli Army Medical Corps
Tirosh A et al. N EJM 364:1315, 2011
Hazard Ratio for the Risk of Coronary Heart Disease
Over 17 Years in Healthy Young Adults, According
to BMI in Adolescence and in Adulthood
37,674 young men, Staff Periodic Exam,
Israeli Army Medical Corps
Tirosh A et al. N EJM 364:1315, 2011
Cardiac Abnormalities in Obesity
• Coronary heart disease
• Diastolic dysfunction
• Left ventricular hypertrophy +/- failure
– eccentric
– concentric
– adipositas cordis (cardiomyopathy of obesity)
• Right ventricular hypertrophy
– Pulmonary hypertension
• obstructive sleep apnea
• central hypoventilation
• thromboembolic disease
– Deep venous thrombosis
• Autonomic dysfunction
• Arrhythmias, prolonged QTc, sudden death
Summary and Conclusions:
Obesity and Co-Morbid Conditions Needing
Assessment
•
•
•
•
•
•
•
•
Cancer risk
Hypertension
Diabetes
Dyslipidemia
Non-alcoholic fatty liver disease
Obstructive sleep apnea-hypopnea
Cardiovascular disease risk
Symptom-based further evaluation prn
Thank You!