“Obesity and Chronic Diseases”
Colorado Center for Health WellnessNational Press Foundation
April 29, 2013
Robert H. Eckel, M.D.Professor of Medicine
Professor of Physiology and BiophysicsCharles A. Boettcher II Chair in Atherosclerosis
University of Colorado Anschutz Medical Campus
Medical Complications of Obesity
Phlebitisvenous stasis
Coronary heart disease
Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndromepulmonary embolismPulmonary hypertension
Gall bladder disease
Gonadal abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndromeerectile dysfunction
Gout
Stroke
Diabetes
Osteoarthritis
Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate, thyroid
Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension
Dyslipidemia
Cataracts
Skin
Idiopathic intracranial hypertension
Pancreatitis
Cognitive impairment
CHF, arrhythmias
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
Renehan AG et al, Lancet 371:569, 2008
- 282,137 incident cases
RR of Cancer in Women with a 5 Kg/m2
Increase in BMI
Renehan AG et al, Lancet 371:569, 2008
- 126,804 incident cases
Obesity and a Strong RR (>1.2) of Cancer
• Men – Esophagus - adenoCa 1.52– Thyroid 1.33– Colon 1.24– Renal 1.24
• Women– Endometrial 1.59– Gallbladder 1.59– Esophageal - adenoCa 1.51– Renal 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
Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634.Caballero AE. Obesity Res. 2003;11:1278-1289.
Lipolytically Active Abdominal Adipose Tissue IL-1, IL-6, TNF
VasodilationShear StressInflammationAtherosclerosisThrombosisCRPPAI-1
Vascular Endothelium
©
Mechanisms Relating Obesity to Hypertension
Narkiewicz K et al Obes Rev 7:155, 2006
Ischemic Heart Disease Mortality vs Usual BP by Age
.
Prospective Studies Collaboration. Lancet. 360:1903, 2002
Systolic Blood Pressure Diastolic Blood Pressure
Usual diastolic BP (mm Hg)
50-59
60-69
70-79
80-89
Age (yr) at risk
40-49
80 90 100 11070
IHD mortality(floating absolute risk and 95% CI)
Usual systolic BP (mm Hg)
50-59
60-69
70-79
80-89
40-49
256
128
64
32
16
8
4
2
1
0120 140 160 180
Age (yr) at risk
BMI and Diabetes: A Large Effect!
BMI, body mass index. Willett WC et al. NEJM 341:427,1999
BMI (kg/m2)
Rel
ativ
e R
isk
Women Men
4
6
5
3
2
1
0<21 22 23 24 25 26 27 28 29 30 <21 22 23 24 25 26 27 28 29 30
Type 2 diabetes
Cholelithiasis
BMI (kg/m2)
Rel
ativ
e R
isk
4
6
5
3
2
1
0
Hypertension
Coronary heart disease23
Risk for Development of T2DM
0102030405060708090
100
Effect of BMI in Women
Attained BMI
<22 22- 23- 24- 25- 27- 29- 31- 33- >35 23 24 25 27 29 31 33 35
NHS. Ann Int Med 122:481, 1995
Age-adjustedRR(%) ofDevelopingT2DM over 14 yr in women aged 30-55 in 1976
Overweight 34%
Obese 31%2007
Natural History of T2DM:A Critical Understanding
75
Insulin resistance
RelativeFunction
(%) 5025
0
Years of Diabetes-15 -10 -5 0 5 10 15 20 25
ß-cell
IGT
Diabetes
100125
Glucose (mg/dL)
350
250
100
-15 -10 -5 0 5 10 15 20 25
Fasting glucose
Post-meal glucose
300
200150
Weyer C et al. J Clin Invest 104: 787, 1999
500
400
300
200
100
00 1 2 3 4 5
Insu
lin S
ecre
tio
n (U
/mL
)
Insulin Action (mg/kg EMBS per minute)
Normal Glucose Tolerance
Insulin Resistance
-C
ell
Fai
lure
ImpairedGlucose
ToleranceType 2
Diabetes
Pathogenesis: ß-Cell Compensationand Decompensation and T2DM
DPP:Mean Weight Change from Baseline
-8
-7-6
-5
-4-3
-2
-10
1
Wei
gh
t C
han
ge
(Kg
)
0 6 12 18 24 30 36 42 48Months
Lifestyle
Metformin
+Placebo
N= 3051 2865 1500 3857.2%
4.2%
NEJM 2002;346: 393
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
All participants-2.8 years
Years from randomization
Cu
mu
lati
ve i
nci
den
ce (
%)
31% 58%
NEJM 346: 393, 2002
DPP: Diabetes Prevention
-10 -8 -6 -4 -2 0 2 4 6
6
11
16
metformin
placebo
Diabetes Risk by Weight Change in the DPP
Change from baseline weight (kg)
Dia
bet
es i
nci
den
ce /
100
per
s-yr
Diabetes 56:1153, 2007
Weight loss explained 64% of the risk reduction from metformin (a weight loss drug?)
Genetic Risk vs. Lifestyle in T2DM?Genetic Risk vs. Lifestyle in T2DM?(TCF7L2 SNP)
Genetic Risk vs. Lifestyle in T2DM?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
8%
Look AHEAD Research Group, 2011
Intensive Lifestyle Intervention (ILI)
Diabetes Support & Education (DSE)
0
10
20
30
40
50
60
70
80
90
100
> 0 % ≥ 10 % ≥ 5 % ≥ 7 %
74%
55%
46%
25%
35%
18%10%
23%
% o
f Par
ticip
ants
≥ 5 % ≥ 0%
18%
26%
45%
≥ 15 %
4%9%
Weight Gain Weight Loss
Percentage of Participants in ILI and DSE Groups Who Met Different Weight Loss
Criteria at Year 4
4-Year Weight Loss Outcomes
-6
-5
-4
-3
-2
-1
0
Overweight
Class I
Class II
Severe
Ch
ang
e in
bo
dy
we
igh
t (%
)
*
* Overweight significantly different from all other groups (p<0.001)
Look AHEAD Research Group, 2011
Revised NCEP ATP III LDL-C Goals
Circulation 2004; 110: 227
Moderately High
190* 0–1 RF’s
160*
2+ RF (10-20%/10 yr)
100* CHD or Risk Equivalent
(>20%/10 yr)
High(Very High)
ConsiderDrug Rx
CHD Risk Category
LDL-C Goal
<100(<70)
<130
<160
2+ RF (<10%/10 yr)
Moderate
Low
<130
130*
* Consider drug options if below goal, but above goal for next higher risk level
Metabolic Syndrome: Residual Risk
• April 2008– 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 avoided?Grady D. A Search for Answers in Russert’s Death. The New York
Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 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)
Normal goose liver
Goose liver after 3 months of overfeeding and inactivity
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
-Neuschwander-Tetri, Hepatology, 2002
“first hit”
Pathogenesis of NAFLD
-Neuschwander-Tetri, Hepatology, 2002
“second hit”
Prevalence of NAFLD
20-30% US adults60% of obese adults
Steatosis
-Neuschwander-Tetri, Hepatology, 2002-McCullough AJ. NAFLD: AASLD Symposium, Nov 9 2001
2-3% US adults20-25% of obese adults
NASH
-Neuschwander-Tetri, Hepatology, 2002-McCullough AJ. NAFLD: AASLD Symposium, Nov 9 2001
Prevalence of NAFLD
Cirrhosis and NAFLD
2-3% of obese adults
-Neuschwander-Tetri, Hepatology, 2002-McCullough AJ. NAFLD: AASLD Symposium, Nov 9 2001
Who should bescreened 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
De Souza AGP et al, Obes Rev 10:1467, 2008
ANC = Adjusted Neck Circ
CVD Mortality and Obesity: Cancer Prevention Study II
0.6
1.0
1.4
1.8
2.2
2.6
3.0 Men (n=84,376)Women (n=217,857)
<18.5 22 25 30 35Body Mass Index (BMI)
Relative Risk of Death
Non-smokers Without known heart disease
Calle EE et al. NEJM 341:1097,1999
28
Metabolic Pathophysiology of Obesity and CVD
• Hypertension
• Dyslipidemia
• Inflammation
• Diabetes
77
4655
106
8997
128
110
83
Abdominal Obesity and Coronary Heart Disease in Women: The Nurses’ Health Study
LowMiddleHigh
High (81.8 - <139.7)
Middle (73.7 - <81.8)
Low (38.1 - <73.7)
(25.2 - <48.8) (22.2 - <25.2) (12.2 - <22.2)
Waist GirthTertiles (cm)
Inci
den
ce
rat
e p
er 1
00,
000
p
ers
on
-yea
rs
Body Mass Index Tertiles (kg/m2)
Follow-up of 8 years
140
120
100
80
60
40
20
0
Adapted from Rexrode KM et al. JAMA 280: 1843, 1998
CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin
Resistance, Hypertension)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Mea
n V
alu
e o
f L
og
CR
P
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
Tirosh A et al. N EJM 364:1315, 2011
37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps
Hazard Ratio for the Risk of Coronary Heart Disease Over 17 Years in Healthy Young Adults, According
to BMI in Adolescence and in Adulthood
Tirosh A et al. N EJM 364:1315, 2011
37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps
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!